Videx EC 125 mg gastro-resistant hard capsule

Videx EC 200 mg gastro-resistant hard capsule

Videx EC 250 mg gastro-resistant hard capsule

Videx EC 400 mg gastro-resistant hard capsule

Each gastro-resistant capsule, hard contains 125 mg, 200 mg, 250 mg or 400 mg of didanosine.

For a full list of excipients, see section 6.1.

Gastro-resistant capsule, hard

125 mg: Gastro-resistant capsules are opaque white and embossed in tan with "6671" on one half, and "BMS 125 mg" on the other half.

200 mg: Gastro-resistant capsules are opaque white and embossed in green with "6672" on one half, and "BMS 200 mg" on the other half.

250 mg: Gastro-resistant capsules are opaque white and embossed in blue with "6673" on one half, and "BMS 250 mg" on the other half.

400 mg: Gastro-resistant capsules are opaque white and embossed in red with "6674" on one half, and "BMS 400 mg" on the other half.

Videx is indicated in combination with other antiretroviral drugs for the treatment of HIV-1 infected patients.

Oral use.

Because didanosine absorption is reduced in the presence of food, Videx gastroresistant capsules should be administered on an empty stomach (at least 2 hours before or 2 hours after a meal) (see section 5.2).

Posology

Videx gastro-resistant capsules may be administered on a once-daily (QD) or a twice-daily (BID) regimen (see section 5.1).

Adults: The recommended daily dose is dependent on patient weight:

• for patients 60 kg: 400 mg per day

• for patients < 60 kg: 250 mg per day

The following table defines the administration schedule for all strengths of the gastro-resistant capsules:

Children older than 6 years: The use of Videx gastro-resistant capsules has not been specifically studied in children. The recommended daily dose (based on body surface area) is 240 mg/m² (180 mg/m² in combination with zidovudine).

Children younger than 6 years: The gastro-resistant capsules should not be opened as there is a potential for inadvertent aspiration. Therefore, this medicine is contraindicated in this age group. Other more appropriate Videx formulations are available.

Dose adjustment

Renal impairment: The following dose adjustments are recommended:

* These strengths of Videx gastro-resistant capsules are not available. An alternative Videx formulation should be used.

The dose should preferably be administered after dialysis (see section 4.4). However, it is not necessary to administer a supplemental dose of Videx_following haemodialysis.

Hepatic impairment: No dose adjustment is required in patients with hepatic impairment (see section 5.2).

Method of administration

To optimise absorption, the gastro-resistant capsule should be taken intact with at least 100 ml of water. Patients should be instructed not to open the capsule to facilitate administration, since this could reduce absorption (see section 5.2).

Hypersensitivity to didanosine or to any of the excipients.

Children younger than 6 years (risk of inadvertent aspiration).

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 whenever possible. If concomitant therapy is unavoidable, close observation is warranted. 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. If symptoms of peripheral neuropathy develop, patients should be switched to an alternative treatment regimen.

Retinal or optic nerve changes: Patients on didanosine have rarely experienced retinal or optic nerve lesions, particularly at doses above those currently recommended. An ophthalmologic examination including visual acuity, color vision, and a dilated fundus examination is to be considered on a yearly basis as well as in case of occurrence of visual changes, in patients treated with didanosine.

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 jiroveci (formerly known as 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 section 4.8).

Osteonecrosis: although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

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 post-natally 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 observation by physicians experienced in the treatment of HIV associated diseases.

Interaction with other medicinal products:

Tenofovir:Co-administration of didanosine and tenofovir disoproxil fumarate results in a 4060% increase in systemic exposure to didanosine that may increase the risk for didanosine-related adverse events (see section 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. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. 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, co-administration of allopurinol and didanosine is not recommended. Patients treated with didanosine who require allopurinol administration should be switched to an alternative treatment regimen (see section 4.5).

Ganciclovir and valganciclovir: Co-administration of didanosine with ganciclovir or valganciclovir may result in didanosine-associated toxicities. Patients should be closely monitored (see section 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, this combination must be avoided.

Co-administration of ribavirin and didanosine is not recommended due to an increased risk of adverse events, in particular of mitochondrial toxicity (see section 4.5).

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.

Patients on sodium restricted diet:

Each 125 mg gastro-resistant capsule contains 0.53 mg sodium.

Each 200 mg gastro-resistant capsule contains 0.85 mg sodium.

Each 250 mg gastro-resistant capsule contains 1.0 mg sodium.

Each 400 mg gastro-resistant capsule contains 1.7 mg sodium.

Specific interaction studies have been conducted with zidovudine, stavudine, ranitidine, loperamide, metoclopramide, foscarnet, trimethoprim, sulfamethoxazole, dapsone and rifabutin, without evidence of interaction.

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 didanosine potentiates the myelosuppressive effects of ganciclovir or zidovudine. Although the magnitude of increase in didanosine exposure when co-administered with valganciclovir has not been established, an increase in didanosine exposure would be anticipated when these agents are co-administered. Appropriate doses of didanosine, when used in combination with ganciclovir or valganciclovir, have not been established. Patients taking didanosine in combination with ganciclovir or valganciclovir should be closely monitored for didanosine-associated toxicities.

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 increases the intracellular triphosphate levels of didanosine. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving didanosine and ribavirin with or without stavudine. Co-administration of ribavirin and didanosine is not recommended (see section 4.4).

Unlike the Videx chewable/dispersible tablets, Videx gastro-resistant capsules do not contain antacids and therefore drug interactions mediated by altered gastric pH are not anticipated when Videx gastro-resistant capsules are co-administered with medicinal products where absorption is influenced by gastric acidity. Specific interaction studies with ciprofloxacin, indinavir, ketoconazole, itraconazole and fluconazole showed no evidence of clinically significant interaction.

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 section 4.4).

When didanosine and allopurinol were co-administered (14 healthy volunteers), the AUC and the C_max 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 section 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 concomitantly and thus increase the potential for didanosine associated undesirable effects. Patients should be closely monitored for didanosine related undesirable effects (see section 4.8).

When didanosine gastro-resistant capsules were administered to opiate-dependent patients chronically treated with methadone, didanosine exposures were decreased compared to historical non-methadone treated controls. This decrease was more pronounced with the didanosine tablets. Therefore, if didanosine is used in combination with methadone, patients should be closely monitored for adequate clinical response.

Ingestion of Videx with food alters the pharmacokinetics of didanosine (see section 5.2).

Pregnancy: There are no adequate data from the use of didanosine 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 section 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 offspring were not impaired. A further study showed that, following oral administration, didanosine and/or its metabolites were excreted in the milk of lactating rats.

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

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 (tablets), 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 gastro-resistant capsule; patients with advanced HIV disease or a history of pancreatitis may be at increased risk of developing pancreatitis (see sections 4.2 and 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 section 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 section 4.4).

Osteonecrosis: cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

The frequency of adverse reactions listed below is defined using the following convention: very common ( 1/10); common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

In an open label clinical study (study148), involving 482 patients treated with Videx tablet plus stavudine and nelfinavir, and in a clinical study (study152) 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.

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 (see section 4.4).

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 section 4.4).

The following events have been identified during post approval use of Videx:

Reproductive system and breast disorders: gynecomastia

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 dialysable 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 2035% of the dose present in the body at the start of dialysis.)

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 two 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 terms 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.

The efficacy of Videx gastro-resistant capsules was evaluated in treatment-naive HIV infected adults as part of a triple regimen in two (48-week) randomised open label clinical trials. Study –152 (n= 466) compared Videx gastro-resistant capsules (QD) plus stavudine and nelfinavir to zidovudine plus lamivudine and nelfinavir. The protocol-defined analysis showed the proportion of patients with HIV RNA levels < 400 copies/ml at week 48 to be similar for the Videx gastro-resistant arm and for the comparator. Similar log₁₀ plasma HIV RNA decreases from baseline (Time Averaged Difference) were observed between treatment arms.

In study -158 (n= 138) the antiviral activity and tolerability of Videx gastro-resistant capsules were compared to tablets, each given QD in combination with stavudine and nelfinavir. At 24 weeks of follow-up, there were similar log₁₀ plasma HIV RNA decreases from baseline (Time Averaged Difference) between treatment arms. The percentages of patients with undetectable viral load (limit of detection < 400 copies/ml) were of the same magnitude between the two Videx arms. Due to the high drop-out rate (> 50%) in this study, no definitive conclusion could be drawn on the long-term data. The efficacy of Videx gastro-resistant capsules has not been established in advanced disease or in highly antiretroviral experienced patients.

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 T69SXX (an amino acid substitution with a 2-amino acid insertion) and multiple nucleoside analogue associated mutations (NAMs).

Adults

Absorption: Didanosine is rapidly degraded at an acidic pH. Therefore, the granules in the Videx gastro-resistant capsules release didanosine into the higher pH of the small intestine.

Compared to the fasting condition, the administration of Videx gastro-resistant capsules with a high fat meal significantly decreases the didanosine AUC (19%) and C_max(46%). Coadministering Videx gastro-resistant capsules with a light meal, 1 hour before or 2 hours after a light meal, results in a significant decrease in both AUC (27%, 24% and 10% respectively) and C_max of didanosine (22%, 15% and 15% respectively) compared to the fasting condition.

In another study, administration of Videx gastro-resistant capsules 1.5, 2 and 3 hours prior to a light meal results in equivalent C_max and AUC values compared to those obtained under fasting conditions.

To minimise the impact of food on the didanosine pharmacokinetics, Videx gastro-resistant capsules should be administered on an empty stomach at least 2 hours before or 2 hours after a meal (see section 4.2).

Relative to administration of intact Videx gastro-resistant capsule on empty stomach, co-administration of didanosine enteric coated beadlets sprinkled on yoghurt and applesauce resulted in a significant decrease in the AUC (20% and 18%, respectively) and C_max (30% and 24%, respectively).

Equivalent values for AUC are observed for the tablet and capsule formulations of Videx in healthy volunteers and subjects infected with HIV. The rate of absorption from Videx capsules is slower compared to the tablet; the value for C_max for the gastro-resistant capsule is 60% of the value for the tablet. The time to reach C_max is approximately 2 hours for the Videx gastro-resistant capsule and 0.67 hour for the Videx tablet.

In 30 patients receiving didanosine 400 mg once daily in the fasted state as Videx gastro-resistant capsules, single dose AUC was 2432 ± 919 ng·h/ml (38%) (mean ± SD [%CV]) and C_max was 933 ± 434 ng/ml (47%).

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, 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. The pharmacokinetics of didanosine has also been studied in 12 non-HIV infected patients 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 didanosine dose were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. AUC and C_max values in these patients with hepatic impairment were similar to those observed in healthy subjects from other studies and are within the pharmacokinetic variability of didanosine (see section 4.2).

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 34 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 section 4.2).

Children

There are no specific pharmacokinetic data from children treated with Videx gastro-resistant capsules.

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 (tablet).

Repeated dose toxicity: Repeat-dose oral toxicity studies revealed evidence of a dose-limiting 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.

Sodium carmellose

Diethyl phthalate

30% methacrylic acid copolymer dispersion (EUDRAGIT L30D-55)

Sodium starch glycolate (Type A)

Talc

Capsule shell:

Gelatin

Sodium laurilsulfate

Titanium dioxide (E171)

Capsule shell imprints (edible ink):

Shellac

Propylene glycol

125 mg:

Potassium hydroxide

Titanium dioxide (E171)

Yellow and red iron oxide (E172)

200 mg:

FD&C Blue #2 Aluminium Lake (E132)

Titanium dioxide (E171)

Yellow iron oxide (E172)

250 mg:

FD&C Blue #2 Aluminium Lake (E132)

400 mg:

Ammonium hydroxide

Simethicone

Red iron oxide (E172)

Not applicable

2 years

Do not store above 25°C.

Polyvinyl Chloride/Polyethylene/ACLAR/Aluminium foil blisters with 10 hard capsules per blister card and 3 cards (30 capsules) per carton or with 10 hard capsules per blister card and 6 cards (60 capsules) per carton.

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

Bristol-Myers Squibb Pharmaceuticals Limited,

Uxbridge Business Park,

Sanderson Road,

Uxbridge,

Middlesex UB8 1DH

10/06/2009

10/06/2009