Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Bristol-Myers Squibb Pharmaceuticals Limited Uxbridge Business Park Sanderson Road Uxbridge Middlesex UB8 1DH
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.
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 co-infected 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 section 4.6).
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.
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 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 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 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.
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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.
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 (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.
Common: peripheral neurologic symptoms (including neuropathy), headache
Very common: diarrhoea
Common: nausea, vomiting, abdominal pain
Common: rash
Common: fatigue
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).
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:
Infections and infestations: sialoadenitis
Blood and lymphatic system disorders: anaemia, leukopenia, thrombocytopenia
Immune system disorders: anaphylactic reaction
Metabolism and nutrition disorders: lactic acidosis, anorexia, diabetes mellitus, hypoglycaemia, hyperglycaemia
Eye disorders: dry eyes, retinal depigmentation, optic neuritis
Gastrointestinal disorders: flatulence, parotid gland enlargement, dry mouth
Hepato-biliary disorders: hepatic steatosis, hepatitis, liver failure (see section 4.4)
Skin and subcutaneous tissue disorders: alopecia
Musculoskeletal, connective tissue and bone disorders: myalgia (with or without increases in creatine phosphokinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, myopathy
General disorders and administration site conditions: asthenia, chills and fever, pain
Investigations: increased/abnormal serum amylase, alkaline phosphatase and creatine phosphokinase
Reproductive system and breast disorders: gynecomastia
Not applicable.
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