ZhengYuan

ZhengYuan is indicated in combination with other antiretroviral drugs for the treatment of HIV-1 infected patients only when other antiretrovirals cannot be used.

Because didanosine absorption is reduced in the presence of food, ZhengYuan gastro-resistant capsules must be administered on an empty stomach (at least 2 hours before or 2 hours after a meal).

Posology

ZhengYuan gastro-resistant capsules are administered on a once daily or a twice daily regimen.

The recommended total daily dose is based on patient body weight (kg):

- for patients weighing at least 60 kg: 400 mg per day

- for patients weighing less than 60 kg: 250 mg per day

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

Special populations

Elderly population: Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see below).

Renal impairment: The following dose adjustments are recommended:

* These strengths of ZhengYuan gastro-resistant capsules are not available. An alternative ZhengYuan formulation is to be used.

The dose should preferably be administered after dialysis. However, it is not necessary to administer a supplemental dose of ZhengYuan following haemodialysis.

Paediatric patients: Since urinary excretion is also a major route of elimination of didanosine in paediatric patients, the clearance of didanosine may be altered in paediatric patients with renal impairment. Although there are insufficient data to recommend a specific dosage adjustment of ZhengYuan in this patient population, a reduction in the dose and/or an increase in the interval between doses must be considered.

Hepatic impairment: No dose adjustment is required in patients with hepatic impairment.

Paediatric population

Paediatric patients older than 6 years: The use of ZhengYuan gastro-resistant capsules has not been specifically studied in paediatric patients. The recommended daily dose (based on body surface area) is 240 mg/m².

Paediatric patients 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 ZhengYuan formulations are available.

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.

Paediatric patients younger than 6 years (risk of inadvertent aspiration).

Co-administration with stavudine due to the potential for serious and/or life-threatening events notably lactic-acidosis, liver function abnormalities, pancreatitis, and peripheral neuropathy.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

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, 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.

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 more than 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 didanosine 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.

Non-cirrhotic Portal Hypertension: Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.

Patients receiving didanosine should be monitored for early signs of portal hypertension (eg, thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. Didanosine should be discontinued in patients with evidence of non-cirrhotic portal hypertension.

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.

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. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Lipoatrophy: on the basis of mitochondrial toxicity, didanosine has been shown to cause loss of subcutaneous fat, which is most evident in the face, limbs, and buttocks.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

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.

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. 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.

Ganciclovir and valganciclovir: Co-administration of didanosine with ganciclovir or valganciclovir may result in didanosine-associated toxicities. Patients should be closely monitored.

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.

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.

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

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:

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

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

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

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

Paediatric population

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 paediatric patient exposed in utero to nucleoside and nucleotide analogues, even HIV-negative paediatric patients, 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.

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

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 ZhengYuan once daily and twice daily (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 ZhengYuan gastro-resistant capsule; patients with advanced HIV disease or a history of pancreatitis may be at increased risk of developing pancreatitis.

Peripheral neurologic symptoms (8%) have been associated with ZhengYuan.

Adverse reactions of moderate or greater severity with at least a possible relationship to treatment regimen (based on investigators' attribution) reported from an open label clinical study (study-148), involving 482 patients treated with ZhengYuan tablet plus stavudine and nelfinavir, and in a clinical study (study-152) evaluating ZhengYuan gastro-resistant capsules as part of a triple regimen in 255 treatment naive HIV infected adults are listed. Also listed are adverse reactions observed post-approval in association with ZhengYuan-containing antiretroviral treatment regimens.

The frequency of adverse reactions listed below is defined using the following convention:

very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

* Adverse reactions observed in post-marketing clinical trials in association with didanosine-containing antiretroviral treatment

** This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to ZhengYuan in randomised controlled clinical trials and compassionate use (n=1873)

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.

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. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Lipoatrophy

Didanosine has been shown to cause loss of subcutaneous fat, which is most evident in the face, limbs and buttocks. The incidence and severity of lipoatrophy are related to cumulative exposure, and is often not reversible when didanosine treatment is stopped. Patients receiving ZhengYuan should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with ZhengYuan should not be continued.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

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.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis have been reported with the use of didanosine.

Paediatric population

Safety data for paediatric patients 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 paediatric patients usually at doses above those recommended.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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 20-35% of the dose present in the body at the start of dialysis.)

Pharmacotherapeutic group: Nucleoside reverse transcriptase inhibitor, ATC Code: J05AF02

Mechanism of action

After didanosine (2', 3'-dideoxyinosine) 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.

Antiviral activity in vitro

Didanosine is an inhibitor of HIV-1 and HIV-2 replication in cultured human cells and cell lines.

Resistance

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

Cross-resistance between didanosine and any antiretroviral class except nucleoside reverse transcriptase inhibitor (NRTIs) is unlikely. Cross-resistance between didanosine and NRTIs is observed in isolates containing multi-resistant mutations such as the Q151M complex, K65R, 3 or more thymidine analog mutations (TAMs), T69ins or multiple nucleoside analogue associated mutations (NAMs).

Clinical results

Using the ZhengYuan tablet formulation, the effect of ZhengYuan twice daily 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 ZhengYuan 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 paediatric patients 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 ZhengYuan administered twice daily. This study showed that 8 weeks of treatment with zidovudine (200 mg) three times daily, ZhengYuan tablets (200 mg) twice daily, or ZhengYuan tablets (200 mg) twice daily plus zidovudine (200 mg) three times daily decreased mean plasma HIV RNA by 0.26, 0.65 and 0.93 log₁₀ copies/ml, respectively.

In antiretroviral naive patients

The efficacy of ZhengYuan tablet or powder was evaluated in treatment-naive HIV infected patients in two (48-week) randomised open label clinical trials.

Study START II (n=205) was a multicenter, randomized, open label study comparing ZhengYuan (200 mg or 125 mg if weight <60 kg) twice daily plus stavudine (40 mg or 30 mg if weight <60 kg) twice daily and indinavir (800 mg) three times daily to zidovudine (200 mg) three times daily plus lamivudine (150 mg) twice daily and indinavir (800 mg) three times daily. Through 48 weeks of treatment, results were in favour of the ZhengYuan 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 ZhengYuan in a once daily dosing regimen has been explored through clinical studies.

Study -148 (n= 756) was a randomised open label study comparing ZhengYuan (400 mg or 250 mg if weight < 60 kg) once daily plus stavudine (40 mg or 30 mg if weight <60 kg) twice daily and nelfinavir (750 mg) three times daily to zidovudine (300 mg) twice daily plus lamivudine (150 mg) twice daily and nelfinavir (750 mg) three times daily (Table 2). After 48 weeks of treatment, results were in favour of the zidovudine, lamivudine and nelfinavir arm compared to ZhengYuan, 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 ZhengYuan-containing arm and 62% for the comparator). However, no formal conclusions can be drawn on this study due to methodological issues.

Table 2: Outcome of Randomized Treatment at Week 48 (Study -148)

^a Number of patients evaluable.

The efficacy of ZhengYuan 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= 511) was a 48-week, randomized, open-label study comparing ZhengYuan gastro-resistant capsules (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) to zidovudine plus lamivudine (300 mg + 150 mg in combination twice daily) and nelfinavir (750 mg three times daily) (Table 3). The protocol-defined analysis showed the proportion of patients with HIV RNA levels < 400 copies/ml at week 48 to be similar for the ZhengYuan 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 ZhengYuan gastro-resistant capsules (400 mg or 250 mg if weight <60 kg) were compared to tablets (400 mg or 250 mg if weight <60 kg), each given once daily in combination with stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily). At 48 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 ZhengYuan 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 ZhengYuan gastro-resistant capsules has not been established in advanced disease or in highly antiretroviral experienced patients.

Table 3: Outcome of Randomized Treatment at Week 48 (Study -152)

^a Number of patients evaluable.

In treatment experienced patients

Study -147 (n= 123) was a randomized open label two-arm study comparing ZhengYuan (400 mg or 250 mg if weight <60 kg) once daily versus ZhengYuan (200 mg or 125 mg if weight <60 kg) twice daily, in combination with stavudine and zidovudine. In the tritherapy setting, the study indicates that, in mostly asymptomatic patients that were stable on their first combination therapy containing ZhengYuan twice daily, the shift to a similar combination therapy with ZhengYuan once daily did not impact at short term (24 weeks) on the existing antiviral efficacy.

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

Compared to the fasting condition, the administration of ZhengYuan gastro-resistant capsules with a high fat meal significantly decreases the didanosine AUC (19%) and C_max(46%). Co-administering ZhengYuan 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 ZhengYuan 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, ZhengYuan gastro-resistant capsules should be administered on an empty stomach at least 2 hours before or 2 hours after a meal.

Relative to administration of intact ZhengYuan 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 ZhengYuan in healthy volunteers and subjects infected with HIV. The rate of absorption from ZhengYuan 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 ZhengYuan gastro-resistant capsule and 0.67 hour for the ZhengYuan tablet.

In 30 patients receiving didanosine 400 mg once daily in the fasted state as ZhengYuan 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 (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. 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.

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.

Paediatric population

There are no specific pharmacokinetic data from paediatric patients treated with ZhengYuan 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.

Not applicable.

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