VIDEX TABLETS 100MG

Active substance: DIDANOSINE

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1.

NAME OF THE MEDICINAL PRODUCT
Videx 100 mg chewable or dispersible tablet

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each chewable or dispersible tablet contains 100 mg of didanosine.
For excipients, see 6.1

3.

PHARMACEUTICAL FORM
Chewable or dispersible tablet:
White tablet, imprinted with “100” on one side and “VIDEX” on the other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Videx is indicated in combination with other antiretroviral drugs for the treatment of HIV infected patients.

4.2

Posology and method of administration

Oral use.
Because didanosine absorption is reduced in the presence of food, Videx should be administered at least 30
minutes before a meal (see 5.2).
Posology
Different tablet strengths of Videx may be administered on a once-daily (QD) or a twice daily (BID) regimen
(see 5.1). To ensure that patients receive a sufficient amount of antacid, and to avoid degradation of
didanosine at an acidic pH, each dose must be given minimally as 2 tablets.

Adults: The recommended daily dose is dependent on patient weight:
ADULT DOSING GUIDELINES
Patient Weight BID(*)
QD(**)
(dose, mg)
(dose, mg)
200
400
≥ 60 kg
< 60 kg
125
250

(*) To ensure that patients receive a sufficient amount of antacid, each dose must be given as 2 tablets (e.g.
the 200 mg BID dose should be given as 2 doses of 2 x 100 mg tablets with approximately 12 hours between
each dose).
(**) To ensure that patients receive a sufficient amount of antacid, each dose must be given as minimally 2
tablets (e.g. the 400 mg QD dose should be given as one dose of (2 x 150 mg + 1 x 100 mg tablets); the
250 mg QD dose as (1 x 100 mg + 1 x 150 mg tablets) (see 5.1)
Children: The recommended daily dose, based on body surface area, is 240 mg/m2/day (180 mg/m2/day in
combination with zidovudine) on a BID or QD schedule.

240 mg/m2/day

180 mg/m2/day

PAEDIATRIC DOSING GUIDELINES
Body Surface Total Daily
BID
2
Area (m )
Dose
(tablets, mg)
(mg/day)
0.5
120
50 + 25
1.0
240
100 + 25
1.5
360
150 + 25
0.5
90
25 + 25
1.0
180
50 + 50
1.5
270
100 + 50

QD
(tablets, mg)
100 + 25
100 + 150
150 + 150 + 50
50 + 50
150 + 25
150 + 100 + 25

Infants younger than 3 months: Insufficient clinical experience exists to recommend a dosing regimen.
Dose adjustment
Pancreatitis: Significant elevations of serum amylase should prompt discontinuation of therapy and careful
evaluation of the possibility of pancreatitis, even in the absence of symptoms of pancreatitis. Fractionation of
amylase may help distinguish amylase of salivary origin. Only after pancreatitis has been ruled out or after
clinical and biological parameters have returned to normal, should dosing be resumed, and then only if
treatment is considered essential. Treatment should be re-initiated with low doses and increased slowly, if
appropriate.
Renal impairment: The following dose adjustments are recommended:

Patient Weight
Creatinine Clearance
(ml/min)
≥ 60
30-59
10-29
< 10

≥ 60 kg
(dose, mg*)
BID
QD

< 60 kg
(dose, mg*)
BID
QD

200
100
(**)
(**)

125
75
(**)
(**)

400
200
150
100

250
150
100
75

(*) To ensure that patients receive a sufficient amount of antacid, each dose must be given as minimally 2
tablets (e.g. the 400 mg QD dose should be given as one dose of (2 x 150 mg + 1 x 100 mg tablets); the
200 mg BID dose as 2 doses of 2 x 100 mg tablets, with approximately 12 hours between each dose).

(**) These patients should only receive a QD regimen.
The dose should preferably be administered after dialysis (see 4.). However, it is not necessary to administer
a supplemental dose of Videx following haemodialysis.
Children: Since urinary excretion is also a major route of elimination of didanosine in children, the
clearance of didanosine may be altered in children with renal impairment. Although there are insufficient
data to recommend a specific dosage adjustment of Videx in this patient population, a reduction in the dose
and/or an increase in the interval between doses should be considered.
Neuropathy: Many patients who present with symptoms of neuropathy and who experience resolution of
symptoms upon drug discontinuation will tolerate a reduced dose of Videx (see 4.4).
Hepatic impairment: No specific dose adjustment can be recommended in patients with hepatic
impairment. These patients should be monitored closely for clinical evidence of didanosine toxicity. Plasma
level monitoring of didanosine may help to identify outliers, but currently available data do not allow
specific recommendations with regard to target plasma levels (see 5.2).
Method of administration
Adults: Patients should take minimally two tablets in each dose, to provide sufficient antacid against acid
degradation of didanosine. The tablets should be thoroughly chewed or dispersed in at least 30 ml of water
prior to consumption. To disperse tablets, stir until a uniform dispersion forms, and drink the entire
dispersion immediately. If additional flavouring is desired, the dispersion may be diluted with 30 ml of clear
apple juice. Stir the further dispersion just prior to consumption.
Children: Children older than 1 year of age should receive a 2-tablet dose, children under
1 year should receive a 1-tablet dose. Tablets should be chewed or dispersed in water prior to consumption,
as described above. When a one tablet dose is required, the volume of water for dispersion should be 15 ml.
Fifteen ml of clear apple juice may be added to the dispersion as a flavouring. Stir the further dispersion just
prior to consumption.

4.3

Contraindications

Hypersensitivity to didanosine or to any of the excipients.

4.4

Special warnings and special precautions for use
Pancreatitis is a known serious complication among HIV infected patients. It has also been
associated with didanosine therapy and has been fatal in some cases. Didanosine should be
used only with extreme caution in patients with a history of pancreatitis. Positive
relationships have been found between the risk of pancreatitis and daily dose of didanosine.
Whenever warranted by clinical conditions, didanosine should be suspended until the
diagnosis of pancreatitis is excluded by appropriate laboratory and imaging techniques.
Similarly, when treatment with other medicinal products known to cause pancreatic toxicity
is required (e.g. pentamidine), didanosine should be suspended during therapy whenever
possible. If concomitant therapy is unavoidable, there should be close observation. Dose
interruption should be considered when biochemical markers of pancreatitis have
significantly increased, even in the absence of symptoms. Significant elevations of
triglycerides are a known cause of pancreatitis and warrant close observation.

Peripheral neuropathy: Patients on didanosine may develop toxic peripheral neuropathy,
usually characterised by bilateral symmetrical distal numbness, tingling, and pain in feet
and, less frequently, hands. Whenever warranted by clinical conditions, didanosine therapy
should be suspended until resolution of symptoms. Many patients tolerate a reduced dose
after resolution of symptoms.
Retinal or optic nerve changes: Children on didanosine have demonstrated retinal or optic
nerve changes on rare occasions, particularly at doses above those recommended. There
have been reports of retinal depigmentation in adult patients. Especially for children,
periodic dilated retinal examinations (every 6 months), or if a change in vision occurs,
should be considered.
Lactic acidosis: lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has
been reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia)
include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise,
loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological
symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated
with pancreatitis, liver failure, or renal failure.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic
hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating
aminotransferase levels. Caution should be exercised when administering nucleoside analogues to
any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for
liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients coinfected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special
risk.
Patients at increased risk should be followed closely. (See also 4.6).
Renal impairment: The half-life of didanosine after oral administration increased from an
average of 1.4 hours in subjects with normal renal function to 4.1 hours in subjects with
severe renal impairment requiring dialysis. After an oral dose, didanosine was not detectable
in peritoneal dialysis fluid; recovery in haemodialysate ranged from 0.6% to 7.4% of the
dose over a 3-4 hour dialysis period. Patients with a creatinine clearance < 60 ml/min may
be at greater risk of didanosine toxicity due to decreased drug clearance. A dose reduction is
recommended for these patients (see 4.2).
Further, the magnesium content of each Videx tablet is 8.6 mEq, which may represent an
excessive load of magnesium to patients with significant renal impairment.
Liver disease: Liver failure of unknown aetiology has occurred rarely in patients on
didanosine. Patients should be observed for liver enzyme elevations and didanosine should
be suspended if enzymes rise to >5 times the upper limit of normal. Rechallenge should be
considered only if the potential benefits clearly outweigh the potential risks.
The safety and efficacy of Videx has not been established in patients with significant
underlying liver disorders. Patients with chronic hepatitis B or C and treated with
combination antiretroviral therapy are at an increased risk for severe and potentially fatal
hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please
refer also to the relevant product information for these medicinal products.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an
increased frequency of liver function abnormalities during combination antiretroviral
therapy and should be monitored according to standard practice. If there is evidence of

worsening liver disease in such patients, interruption or discontinuation of treatment must be
considered.
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency
at the time of institution of combination antiretroviral therapy (CART), an inflammatory
reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious
clinical conditions, or aggravation of symptoms. Typically, such reactions have been
observed within the first few weeks or months of initiation of CART. Relevant examples are
cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and
Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and
treatment instituted when necessary.
Lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy has been
associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term
consequences of these events are currently unknown. Knowledge about the mechanism is
incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs
has been hypothesised. A higher risk of lipodystrophy has been associated with individual
factors such as older age, and with drug related factors such as longer duration of
antiretroviral treatment and associated metabolic disturbances. Clinical examination should
include evaluation for physical signs of fat redistribution. Consideration should be given to
the measurement of fasting serum lipids and blood glucose. Lipid disorders should be
managed as clinically appropriate (see 4.8).
Infants younger than 3 months: Insufficient clinical experience exists to recommend a
dosing regimen.
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated
in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been
reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse events reported are haematological
disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia).
These events are often transitory. Some late-onset neurological disorders have been reported
(hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are
transient or permanent is currently unknown. Any child exposed in utero to nucleoside and
nucleotide analogues, even HIV-negative children, should have clinical and laboratory
follow-up and should be fully investigated for possible mitochondrial dysfunction in case of
relevant signs or symptoms. These findings do not affect current national recommendations
to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Opportunistic infections: Patients receiving didanosine or any antiretroviral therapy may
continue to develop opportunistic infections and other complications of HIV infection or
therapy. They therefore should remain under close clinical observation by physicians
experienced in the treatment of patients with HIV associated diseases.
Interaction with other medicinal products:
Tenofovir: Co-administration of didanosine and tenofovir disoproxil fumarate results in a
40-60% increase in systemic exposure to didanosine that may increase the risk for
didanosine-related adverse events (see 4.5). Rare cases of pancreatitis and lactic acidosis,
sometimes fatal, have been reported.
A reduced didanosine dose (250 mg) has been tested to avoid over-exposure to didanosine in
case of co-administration with tenofovir disoproxil fumarate, but this has been associated

with reports of high rate of virological failure and of emergence of resistance at early stage
within several tested combinations.
Co-administration of didanosine and tenofovir disoproxil fumarate is therefore not
recommended, especially in patients with high viral load and low CD4 cell count. If this
combination is judged strictly necessary, patients should be carefully monitored for efficacy
and didanosine related adverse events.
Allopurinol: Co-administration of didanosine and allopurinol results in increased systemic
exposure to didanosine, which can result in didanosine-associated toxicity. Therefore, coadministration of allopurinol and didanosine is not recommended. Patients treated with
didanosine who require allopurinol administration should be switched to an alternative
treatment regimen (see 4.5).
Not recommended combinations: pancreatitis (fatal and nonfatal) and peripheral neuropathy
(severe in some cases) have been reported in HIV infected patients receiving didanosine in
association with hydroxyurea and stavudine. Hepatotoxicity and hepatic failure resulting in
death were reported during postmarketing surveillance in HIV infected patients treated with
antiretroviral agents and hydroxyurea; fatal hepatic events were reported most often in
patients treated with stavudine, hydroxyurea and didanosine. Hence, hydroxyurea should not
be used in the treatment of HIV infection.
Triple nucleoside therapy: There have been reports of a high rate of virological failure and
of emergence of resistance at an early stage when didanosine was combined with tenofovir
disoproxil fumarate and lamivudine as a once daily regimen.
Phenylketonurics: Videx tablets contain 36.5 mg phenylalanine (from the aspartame).
Therefore, the use of Videx in phenylketonuria patients should be considered only if clearly
indicated.
Sorbitol: Videx tablets contain sorbitol (342 mg, 333 mg, 316 mg and 300 mg for the
25 mg, 50 mg, 100 mg and 150 mg tablets respectively). Therefore the use of Videx tablets
in patients with fructose intolerance should be considered only if clearly indicated.

4.5

Interaction with other medicinal products and other forms of interaction
Specific drug interaction studies have been conducted with zidovudine, stavudine,
ranitidine, loperamide, metoclopramide, foscarnet, trimethoprim, sulfamethoxazole,
dapsone, and rifabutin without evidence of interaction. Based upon the results from a study
with ketoconazole, it is recommended that medicines which can be affected by stomach
acidity (e.g. oral azoles such as ketoconazole and itraconazole), be given at least 2 hours
prior to dosing with didanosine.
Administration of didanosine 2 hours prior to, or concurrent with, ganciclovir was
associated with a mean increase of 111% in the steady state AUC for didanosine. A minor
decrease (21%) in the steady state AUC of ganciclovir was seen when didanosine was given
2 hours prior to ganciclovir, but not when both medicines were given simultaneously. There
were no changes in renal clearance for either drug. It is not known whether these changes
are associated with alterations in either the safety of didanosine or the efficacy of
ganciclovir. There is no evidence that Videx potentiates the myelosuppressive effects of
ganciclovir or zidovudine.

Co-administration of didanosine with medicines that are known to cause peripheral
neuropathy or pancreatitis may increase the risk of these toxicities. Patients who receive
these medicines should be carefully observed.
Based on in vitro data, ribavirin may increase the intracellular triphosphate levels of
didanosine and potentially increase the risk of adverse reactions (see 4. and 4.8); therefore,
unless further clinical data are available, caution should be used, if these drugs need to be
co-administered.
As with other products containing magnesium and / or aluminium antacid components,
Videx tablets should not be taken with any tetracycline antibiotic. Likewise, plasma
concentrations of some quinolone antibiotics (e.g. ciprofloxacin) are decreased by
administration with antacids contained in or administered with Videx. It is recommended
that medicines that may interact with antacids should not be administered within 2 hours of
taking Videx tablets.
When didanosine gastro-resistant capsules were administered 2 hours prior to or
concurrently with tenofovir disoproxil fumarate, the AUC for didanosine was on average
increased by 48% and 60% respectively. The mean increase in the AUC of didanosine was
44% when the buffered tablets were administered 1 hour prior to tenofovir. In both cases
the pharmacokinetic parameters for tenofovir administered with a light meal were
unchanged. The co-administration of didanosine and tenofovir disoproxil fumarate is not
recommended (see 4.4).
When didanosine and allopurinol were co-administered (14 healthy volunteers), the AUC
and the Cmax for didanosine significantly increased 105% and 71%, respectively. Therefore,
co-administration of allopurinol (a xanthine oxidase inhibitor) with didanosine is not
recommended. Patients treated with didanosine who require allopurinol administration
should be switched to an alternative treatment regimen (see 4.4). Xanthine oxidase is an
enzyme involved in the metabolism of didanosine. Other inhibitors of xanthine oxidase may
increase exposure to didanosine when administered together and thus increase the potential
for didanosine associated undesirable effects. Patients should be closely monitored for
didanosine related undesirable effects (see 4.8).
Ingestion of Videx with food alters the pharmacokinetics of didanosine (see 5.2).
4.6.

Pregnancy and lactation

Pregnancy: There are no adequate and well-controlled studies in pregnant women and it is not known
whether didanosine can cause foetal harm or affect reproductive capacity when administered during
pregnancy. Lactic acidosis (see 4.4), sometimes fatal, has been reported in pregnant women who received the
combination of didanosine and stavudine with or without other antiretroviral treatment. Therefore, the use of
didanosine during pregnancy should be considered only if clearly indicated, and only when the potential
benefit outweighs the possible risk.
Teratology studies in rats and rabbits did not produce evidence of embryotoxic, foetotoxic, or teratogenic
effects. A study in rats showed that didanosine and/or its metabolites are transferred to the foetus through the
placenta.
Lactation: It is not known whether didanosine is excreted in human milk. It is recommended that women
taking didanosine do not breast-feed because of the potential for serious adverse reactions in nursing infants.
At the 1000 mg/kg/day dose levels in rats, didanosine was slightly toxic to females and pups during mid and
late lactation (reduced food intake and body weight gains), but the physical and functional development of

the subsequent offsprings were not impaired. A further study showed that, following oral administration,
didanosine and/or its metabolites were excreted into the milk of lactating rats.

4.7

Effects on ability to drive and use machines

No effects on the ability to drive and use machines have been observed.

4.8

Undesirable effects

Adults: Most of the serious adverse events observed have generally reflected the recognised clinical course
of HIV infection.
In data collected earlier involving monotherapy regimens, no different safety concerns were seen compared
to the triple regimen data presented below. In comparative studies between Videx QD and BID, no
significant difference in terms of incidence of pancreatitis and peripheral neuropathy has been shown.
Pancreatitis, which may be fatal in some cases, was reported in <1% of the patients receiving Videx gastroresistant capsule; patients with advanced HIV disease or a history of pancreatitis may be at increased risk of
developing pancreatitis (see sections 4.2 and section 4.4).
Peripheral neurologic symptoms (8%) have been associated with Videx (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see 4.4).
Lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy has been associated
with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and
facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and
dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see
4.4).
In an open label clinical study (study-148), involving 482 patients treated with Videx tablet plus stavudine
and nelfinavir, and in a clinical study (study-152) evaluating Videx gastro-resistant capsules as part of a
triple regimen in 255 treatment naive HIV infected adults, the following undesirable effects (moderate to
severe), which occured at a frequency of 2%, and which are considered possibly related to study regimen
based on the investigators' attribution, were reported:
Nervous system disorders:
common: peripheral neurologic symptoms (including neuropathy), headache
Gastrointestinal disorders:
very common: diarrhoea
common: nausea, vomiting, abdominal pain
Skin and subcutaneous tissue disorders:
common: rash
General disorders:
common: fatigue



Laboratory abnormalities:
Laboratory abnormalities (grade 3-4) reported in studies -148 (tablets) and -152 (gastro-resistant capsules)
included increase of lipase in 7% and 5% respectively, increase of ALT in 3% and 6% respectively, increase
of AST in 3% and 5%, respectively, increase in uric acid in 2% in both studies, and increase of bilirubin in
1% and <1% respectively, of the patients. Neutropenia (grade 3-4) was reported in 2% in both studies 148

and 152, anemia in <1% and 1% in study 148 and in study 152 respectively, and thrombocytopenia in 1%
and <1%, respectively, of the patients.
Children: Safety data for children were generally similar to those seen in adults. A higher haematotoxicity
has been reported with the combination with zidovudine compared to didanosine monotherapy. Retinal or
optic nerve changes have been reported in a small number of children usually at doses above those
recommended. It is recommended that children on didanosine treatment undergo dilated retinal examination
every 6 months or if a change in vision occurs.
Postmarketing:
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis
have been reported with the use of nucleoside analogues (see 4.4).
The following events (frequency rare to very rare) have been identified during post approval use of Videx:
General disorders and administration site conditions: asthenia, chills and fever, pain Gastrointestinal
disorders: flatulence, parotid gland enlargement, dry mouth
Metabolism and nutrition disorders: lactic acidosis, anorexia, diabetes mellitus, hypoglycaemia,
hyperglycaemia
Skin and subcutaneous tissue disorders: alopecia
Hepatobiliary disorders: hepatic steatosis, hepatitis, liver failure (see section 4.4).
Infections and infestations: sialoadenitis
Blood and lymphatic system disorders: anaemia, leukopenia, thrombocytopenia
Immune system disorders: anaphylactic reaction
Eye disorders: dry eyes, retinal depigmentation, optic neuritis
Musculoskeletal, connective tissue and bone disorders: myalgia (with or without increases in creatine
phosphokinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, myopathy
Investigations: increased/abnormal serum amylase, alkaline phosphatase and creatine phosphokinase

4.9

Overdose

There is no known antidote for didanosine overdosage. Experience in early studies, in which didanosine was
initially administered at doses ten times the recommended doses, indicates that the anticipated complications
of overdosage could include pancreatitis, peripheral neuropathy, hyperuricemia and hepatic dysfunction.
Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by haemodialysis. (The
fractional removal of didanosine during an average haemodialysis session of 3 to 4 hours was approximately
20-35% of the dose present in the body at the start of dialysis.)

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic Properties
Nucleoside reverse transcriptase inhibitor: ATC Code: J05AF02
Didanosine (2',3'-dideoxyinosine) is an inhibitor of the in vitro replication of HIV in
cultured human cells and cell lines. After didanosine enters the cell, it is enzymatically
converted to dideoxyadenosine-triphosphate (ddATP), its active metabolite. In viral nucleic
acid replication, incorporation of this 2',3'-dideoxynucleoside prevents chain extension, and
thereby inhibits viral replication.
In addition, ddATP inhibits HIV-reverse transcriptase by competing with dATP for binding
to the enzyme's active site, preventing proviral DNA synthesis.

The relationship between in vitro susceptibility of HIV to didanosine and clinical response
to therapy has not been established. Likewise, in vitro sensitivity results vary greatly and
methods to establish virologic responses have not been proven.
Using the Videx tablet formulation, the effect of Videx BID administration, alone or in
combination with zidovudine, was evaluated in several major randomised, controlled
clinical trials (ACTG 175, ACTG 152, DELTA, CPCRA 007). These trials confirmed the
reduced risk of HIV disease progression or death with Videx tablets therapy, alone or in
combination with zidovudine, as compared with zidovudine monotherapy in HIV infected
individuals, including symptomatic and asymptomatic adults with CD4 counts < 500
cells/mm3 and children with evidence of immunosuppression. The primary demonstration of
clinical benefits of didanosine has been made through the ACTG 175 trial with the buffered
tablet formulation of Videx administered twice daily (BID). This study showed that eight
weeks of treatment with zidovudine, Videx tablets BID, or Videx tablets BID plus
zidovudine decreased mean plasma HIV RNA by 0.26, 0.65 and 0.93 log10 copies/ml,
respectively. In the tritherapy setting, the combination of Videx (200 mg) BID plus
stavudine and indinavir has been compared to zidovudine plus lamivudine and indinavir in a
randomised open label study (START II, n= 205): through 48 weeks of treatment, results
were in favour of the Videx arm. However, no formal conclusion can be drawn on the
equivalence of the 2 regimens.
Since didanosine exhibits a very long intracellular half-life (> 24 hours), permitting the
accumulation of its pharmacologically active ddATP-moiety for extended time periods,
administration of the total daily dose of Videx in a QD dosing regimen has been explored
through clinical studies.
Several clinical studies have been performed with Videx (tablet) administered once daily
(QD), including the following:
In the tritherapy setting, the randomised open label study –147 indicates that, in mostly
asymptomatic patients (n= 123) that were stable on their first combination therapy
containing Videx BID, the shift to a similar combination therapy with Videx QD did not
impact at short term (24 weeks) on the existing antiviral efficacy.
The randomised open label study –148 (n= 756) compared Videx QD plus stavudine and
nelfinavir to zidovudine plus lamivudine and nelfinavir. After 48 weeks of treatment, results
were in favour of the zidovudine (BID), lamivudine and nelfinavir arm compared to Videx
(QD), stavudine and nelfinavir arm in term of proportion of patients with undetectable viral
load (the proportion of patients with HIV RNA copies < 400 copies/ml was 53% for the
Videx-containing arm and 62% for the comparator). However, no formal conclusions can be
drawn on this study due to methodological issues.
Current evidence indicates that the incidence of resistance to didanosine is an infrequent
event and the resistance generated is modest in degree. Didanosine-resistant isolates have
been selected in vivo and are associated with specific genotype changes in the reverse
transcriptase codon region (codons L74V (most prevalent), K65R, M184V and
T69S/G/D/N). Clinical isolates that exhibited a decrease in didanosine susceptibility
harbored one or more didanosine-associated mutations. Mutant viruses containing the L74V
substitution show a decline in viral fitness and these mutants quickly revert to wild type in
the absence of didanosine. Cross-resistance between didanosine and protease inhibitors or
non nucleoside reverse transcriptase inhibitor is unlikely. Cross-resistance between
didanosine and nucleoside reverse transcriptase inhibitor is observed in isolates containing
multi-resistant mutations such as Q151M and T69S-XX (an amino acid substitution with a
2-amino acid insertion) and multiple nucleoside analogue associated mutations (NAMs).

5.2

Pharmacokinetic Properties
Adults
Absorption: Didanosine is rapidly degraded at an acidic pH. Therefore, the tablets contain
buffering agents designed to increase gastric pH. The administration of didanosine with a
meal results in a significant decrease (about 50%) in bioavailability. Videx tablets should be
administered at least 30 minutes before a meal. A study in 10 asymptomatic HIV
seropositive patients demonstrated that administration of Videx tablets 30 min to 1 hour
before a meal did not result in any significant changes in the bioavailability of didanosine
compared to administration under fasting conditions. Administration of the tablets 1 to 2
hours after a meal was associated with a 55% decrease in Cmax and AUC values, which was
comparable to the decrease observed when the formulation was given immediately after a
meal.
In 30 patients receiving didanosine 400 mg once daily in the fasted state as Videx buffered
tablets, single dose AUC was 2516 ± 847 ng·h/ml (34%) (mean ± SD [%CV]) and Cmax was
1475 ± 673 ng/ml (46%).
Distribution: The volume of distribution at steady state averages 54 l, suggesting that there
is some uptake of didanosine by body tissues. The level of didanosine in the cerebrospinal
fluid (CSF), one hour after infusion, averages 21% of that of the simultaneous plasma level.
Biotransformation: The metabolism of didanosine in man has not been evaluated. However,
based on animal studies, it is presumed that it follows the same pathways responsible for the
elimination of endogenous purines.
Elimination: The average elimination half-life after IV administration of didanosine is
approximately 1.4 hours. Renal clearance represents 50% of total body clearance
(800 ml/min), indicating that active tubular secretion, in addition to glomerular filtration, is
responsible for the renal elimination of didanosine. Urinary recovery of didanosine is
approximately 20% of the dose after oral treatment. There is no evidence of didanosine
accumulation after the administration of oral doses for 4 weeks.
Hepatic impairment: No significant changes in the pharmacokinetics of didanosine were
observed among haemophiliac patients with chronic, persistent elevations in liver function
enzymes (n=5), which may be indicative of impaired hepatic function; haemophiliac patients
with normal or less severe increases in liver function enzymes (n=8); and non-haemophiliac
patients with normal enzyme levels (n=8) following a single IV or oral dose. No conclusion
can be drawn regarding the metabolism of didanosine, which may be altered in patients with
severe hepatic impairment (see 4.2).
Children
Absorption: Variability in the amount of didanosine absorbed in children is greater than in
adults. The absolute bioavailability of didanosine administered orally was approximately
36% after the first dose and 47% at steady state.

Distribution: The CSF didanosine level averages 46% of that of the simultaneous plasma
level after IV administration of doses of 60 or 90 mg/m2 and equivalent oral doses of 120 or
180 mg/m2. Measurable concentrations of didanosine in the CSF were detectable for up to
3.5 hours after dosing.
Elimination: The average elimination half-life after IV didanosine administration is
approximately 0.8 hours. Renal clearance represents approximately 59% of the total body
clearance (315 ml/min/m2), indicating that both renal and nonrenal pathways are involved in
the elimination. Urinary recovery of didanosine is approximately 17% of dose after oral
treatment. There is no evidence of didanosine accumulation after oral administration for an
average of 26 days.

5.3

Pre-clinical Safety Data
The lowest dose to cause death in acute toxicity studies in the mouse, rat and dog was
greater than 2000 mg/kg which is equivalent to approximately 300 times the maximum
recommended human dose.
Repeated dose toxicity: Repeat-dose oral toxicity studies revealed evidence of a doselimiting skeletal muscle toxicity in rodents (but not in dogs) following long-term (> 90 days)
dosing with didanosine at doses that were approximately 1.2 - 12 times the estimated human
dose. Additionally, in repeat dose studies, leukopenia was observed in dogs and rats, and
gastrointestinal disturbances (soft stool, diarrhoea) were seen in dogs at doses approximately
5 - 14 times the maximum human dose.
Carcinogenicity: In the carcinogenicity studies, non-neoplastic alterations have been
observed including skeletal muscle myopathy, hepatic alterations and an exacerbation of
spontaneous age-related cardiomyopathy.
Lifetime dietary carcinogenicity studies were conducted in mice and rats for 22 or 24
months, respectively. No drug-related neoplasms were observed in any didanosine-treated
groups of mice during, or at the end of, the dosing period. In rats, statistically significant
increased incidences of granulosa cell tumours in females receiving the high dose, of
subcutaneous fibrosarcomas and histiocytic sarcomas in males receiving the high dose and
of haemangiomas in males receiving the high and intermediate dose of didanosine were
noted. The drug-relationship and clinical relevance of these statistical findings were not
clear.
Genotoxicity: Results from the genotoxicity studies suggest that didanosine is not mutagenic
at biologically and pharmacologically relevant doses. At significantly elevated
concentrations in vitro, the genotoxic effects of didanosine are similar in magnitude to those
seen with natural DNA nucleosides.
Reproduction: In rats, didanosine did not impair the reproduction ability of male or female
parents following treatment prior to and during mating, gestation and lactation at daily
didanosine doses up to 1000 mg/kg/day. In a perinatal and postnatal reproduction study in
rats, didanosine did not induce toxic effects.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of Excipients

Calcium carbonate, magnesium hydroxide, aspartame, sorbitol, microcrystalline cellulose,
crospovidone, mandarin orange flavour (tangerine oil, mandarin oil, gum arabic, alpha tocopherol,
colloidal silica) and magnesium stearate.

6.2

Incompatibilities
Not applicable.

6.3

Shelf-Life
2 years.
After dispersion in water, the dispersion is physically and chemically stable for 1 hour.

6.4

Special Precautions for Storage
Do not store above 30°C. Keep the container tightly closed in order to protect from
moisture.

6.5

Nature and Content of Container
High-density polyethylene bottle with child-resistant cap.
Package size: 60 tablets per bottle.

6.6

Instruction for Use, Handling and Disposal
No special requirements.

7.

MARKETING AUTHORISATION HOLDER
Bristol-Myers Squibb Pharmaceuticals Limited
Uxbridge Business Park
Sanderson Road
Uxbridge,
Middlesex
UB8 1DH

8.

MARKETING AUTHORISATION NUMBER(S)
PL 11184/0010

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
17th February 1994 / 30 May 2002

10

DATE OF REVISION OF THE TEXT
25/11/2006

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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