Didanosine
Didanosine is a synthetic, purine nucleoside analogue active against the Human Immuno- deficiency Virus (HIV). The chemical name for didanosine is 2', 3'-dideoxyinosine; it is also called ddI. It has the following structural formula: Didanosine is a white, crystalline, non-hygroscopic powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2 daltons. The aqueous solubility of didanosine at 25oC and pH of approximately 6 is 27.3mg/mL. CAS Registry Number: 69655-05-6 Videx Paediatric Powder for Oral Solution contains only didanosine. Videx EC capsules contain didanosine, sodium starch glycollate, carmellose sodium, methacrylic acid copolymer, diethyl phthalate, talc, sodium hydroxide, gelatin, titanium dioxide, silicon dioxide and sodium lauryl sulfate. The capsules are imprinted with Tan Ink SW-8010 ARTG No 4409 (125 mg capsules), Tekprint SB-4020 Green Ink ARTG No 2652 (200mg capsules), Tekprint SB-6018 Blue Ink ARTG No 2653 (250mg capsules), and Opacode S-1-15034 Red ARTG No 2861 (400mg capsules).
Pharmacokinetics
Didanosine is rapidly degraded at acidic pH. The paediatric powder must be administered with a buffering agent.
Adult Absorption Information
Peak plasma concentrations and area under the plasma concentration versus time curves were proportional to dose over the range of 0.4-16.5mg/kg IV and 0.8-10.2mg/kg PO. Plasma concentrations in excess of 2400 ng/mL (10M) were achieved at intravenous doses of 3mg/kg or oral doses in excess of 6mg/kg. In patients administered a reconstituted lyophilized formulation with antacid (PO), the absolute bioavailability of didanosine is approximately 40%. Pharmacokinetic parameters at steady state are not significantly different from values obtained after a single IV or PO dose. Didanosine is protected against degradation by stomach acid either by the use of an enteric coating (Videx EC) or by administration with antacid (Videx). The enteric-coating dissolves when the beadlets empty in to the small intestine, the site of drug absorption. In healthy volunteers, as well as subjects infected with HIV, the area under the plasma concentration time curve (AUC) is equivalent for didanosine administered as the Videx EC capsule formulation relative to Videx buffered tablets. The peak plasma concentration (CMAX) of didanosine, administered as Videx EC capsules, is reduced approximately 40% relative to Videx buffered tablets. The time to peak concentration (TMAX) increases from approximately 0.67 hours for Videx buffered tablets to 2.0 hours for Videx EC capsules. Plasma concentrations decline with a similar apparent half-life after oral dosing with either formulation. All Videx formulations should be administered on an empty stomach. The pharmacokinetics of didanosine have not been studied in patients over 65 years of age. Adult Distribution Information The volume of distribution (of IV didanosine) at steady state averaged 54 L, suggesting that there is some uptake of didanosine by body tissues. In a study of 5 adults, the level of didanosine in the cerebrospinal fluid one hour after infusion of didanosine averaged 21% of that of the simultaneous plasma level.
Adult Elimination Information
The average elimination half-life after didanosine was given IV is approximately 1.4 hour. Total body clearance of didanosine by the same route averaged 800 mL/min. Renal clearance represented 50% of total body clearance (400 mL/min), when didanosine was given either intravenously or orally, indicating that active tubular secretion, in addition to glomerular filtration, is responsible for the renal elimination of didanosine. Urinary recovery of didanosine was approximately 55% and 20% of dose after IV and PO treatment, respectively. There is no evidence of accumulation of didanosine after the administration of IV doses for 14 days or PO doses for 4 weeks.
Paediatric Absorption Information
Peak plasma concentrations and area under the plasma concentration versus time curves appear to be proportional to dose over the range of 40-90mg/m2 IV and 80-180mg/m2 PO. Peak plasma concentrations (CMAX) averaging 2300 ng/mL were achieved with intravenous doses of 90mg/m2, while mean CMAX values at steady state at the highest PO doses given (180mg/m2) were 1700 ng/mL. Variability in the amount of didanosine absorbed in this population of patients is greater than in adults. The absolute bioavailability of didanosine administered orally as a reconstituted lyophilized formulation with antacid is approximately 36% and 47% after the first dose and at steady state, respectively.
Paediatric Distribution Information
The volume of distribution of didanosine when given intravenously averaged 35.6 L/m2. The didanosine cerebrospinal fluid (CSF)/plasma ratio has been evaluated in seven paediatric patients with AIDS or symptomatic HIV infection. The level of didanosine in the cerebrospinal fluid averages 46% of that of the simultaneous plasma level after the administration of IV doses equivalent to 60 or 90mg/m2 and PO doses equivalent to 120 or 180mg/m2. Measurable concentrations of didanosine in the CSF were detectable for up to 1.5 to 3.5 hours.
Paediatric Elimination Information
The average elimination half-life after didanosine was given IV is approximately 0.8 hours. Total body clearance of didanosine, when given intravenously averaged 532 mL/min.m2. Renal clearance represented approximately 59% of the total body clearance (315 mL/min.m2) when given intravenously, indicating that both renal and non-renal pathways are involved in the elimination of didanosine. Mean renal clearance values ranged from 190 to 319 mL/min.m2 after the first oral dose and from 231 to 265 mL/min.m2 at steady state. Urinary recovery of didanosine was approximately 60% and 17% of dose after IV and PO treatment, respectively. There is no evidence of accumulation of didanosine after the administration of oral doses for an average of 26 days.
Metabolism
In dogs given a single IV or PO dose of 14C-radiolabeled didanosine, extensive metabolism occurred. Three putative metabolites were tentatively identified as hypoxanthine, xanthine and uric acid. The major metabolite isolated in the urine, representing approximately 61% of the administered radiolabel after oral administration, was identified as allantoin. A similar metabolic profile was obtained using an isolated perfused rat liver preparation. The metabolic fate of the dideoxyribose moiety, released subsequent to enzymatic or chemical hydrolysis of the glycosidic bond, has not been detered. Based on data from animal studies, it is presumed that the metabolism of didanosine in man will occur by the same pathways responsible for the elimination of endogenous purines. However, the metabolism of didanosine in man has not been evaluated. The intracellular half-life of ddATP, the metabolite presumed to be responsible for the anti-retroviral activity of didanosine, is reported to be 8-24 hr in vitro. The half-life of intracellular ddATP in vivo has not been measured.
In vitro
human plasma protein binding is less than 5% with didanosine, indicating that drug interactions involving binding site displacement are not anticipated.
Mechanism of Action
Didanosine, a nucleoside analogue of deoxyadenosine, is an inhibitor of the in vitro replication of HIV (also known as HTLV III or LAV) in human primary cell cultures and in established cell lines. After didanosine enters the cell, it is converted by cellular enzymes to the active antiviral metabolite, dideoxyadenosine triphosphate (ddATP). The intracellular half-life of ddATP, calculated from results obtained from in vitro cell culture studies, varied from 8 to 24 hours. A common feature of dideoxynucleosides (the class of compounds to which didanosine belongs) is the lack of a free 3'-hydroxyl group. In nucleic acid replication the 3'-hydroxyl of a naturally occurring nucleoside is the acceptor for covalent attachment of subsequent nucleoside 5'-monophosphates; its presence is therefore requisite for continued DNA chain extension. Because ddATP lacks a 3'-hydroxyl group, incorporation of ddATP into viral DNA leads to chain termination and, thus, inhibition of viral replication. In addition, ddATP further contributes to inhibition of viral replication through interference with HIV-RNA dependent DNA polymerase (reverse transcriptase) by competing with the natural nucleoside triphosphate, dATP, for binding to the active site of the enzyme.
Microbiology
The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in man or clinical response to therapy has not been established. In vitro sensitivity results vary greatly depending upon the time between virus infection and didanosine treatment, the particular assay used, the cell type employed, and the laboratory performing the test. In addition, the reliability of methods currently available to establish virological responses in clinical trials has not been proven. Didanosine has in vitro antiviral activity against HIV-1 and 2 with ID50 values usually ranging from 0.01 to 0.1 M. Complete protection of ATH8 cells infected with HIV-1 (HTLV IIIB) at 10 M didanosine has been reported. The expression of p24 gag protein in H9 cells was blocked with 10 M didanosine. In infected human MT-2 cells in culture, didanosine has been shown to be active against both HIV-1 (ID50 1 M) and HIV-2 (ID50 10 M), while zidovudine, in this same assay system had ID50 values of 0.3 M and >100 M against HIV-1 and HIV-2, respectively. In a quantitative plaque reduction assay using HT4-6C cells, didanosine has also been shown to be active against both HIV-1 (ID50 2.1 M) and HIV-2 (ID50 5.6 M). The activities of zidovudine in this same system were 0.05 M and 0.08 M against HIV-1 and HIV-2, respectively. In this same assay system, didanosine has shown activity against zidovudine-resistant HIV-1 strains isolated from patients who had received long-term therapy with zidovudine. The development of resistance to didanosine has not been adequately studied and the frequency of didanosine-resistant isolates in the general population is unknown. The results of cytotoxicity studies in various cell lines have shown little cytotoxic action with didanosine. Also, in cultured human bone marrow progenitor cells the IC50 values for growth inhibition were >100 M for didanosine. For zidovudine, IC50 values in these same assays ranged from 0.13 M to 5 M. SCID mice transplanted with human fetal tissue to allow development of an immune system of human origin (SCID-Hu) have been infected with HIV and have shown subsequent viraemia. The viraemia has been prevented with antiretroviral agents; PD50 values of zidovudine and didanosine were 66 and 13mg/kg/day, respectively.
Videx has been studied in both antiretroviral-experienced and -naive patients as monotherapy and in double and triple-combination regimens. Once-daily dosing of didanosine produces a pharmacokinetic profile that is substantially different from that observed with twice-daily dosing of didanosine (see CLINICAL PHARMACOLOGY). Further, VIDEX EC and the VIDEX (didanosine) buffered formulation produce substantially different pharmacokinetic profiles when dosed once daily. Therefore, controlled clinical trials were conducted with both formulations to evaluate the safety and efficacy of once-daily dosing of didanosine. There is no evaluable long-term clinical information that directly compares the efficacy of the two once-daily didanosine formulations. A small clinical study that was conducted to address this issue was not interpretable due to the small number of patients who completed the study.
Study AI454-152 is an ongoing, 48-week, randomised, open-label study comparing VIDEX EC (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (200 mg twice daily) plus lamivudine (150 mg twice daily) combination tablets plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV RNA <400 and <50 copies/mL and not meeting any criteria for treatment failure (eg, virologic failure, discontinuation for any reason, or AIDS-defining event) through 48 weeks are shown in Figure 1.
Percent of Patients
0 12 24 36 48
StudyWeek
]
< 400 c/mL
| VIDEX EC: 258 | 258 | 238 | 167 |
| Z/L: 253 | 253 | 232 | 166 |
VIDEX EC+stavudine+nelfinavir zidovudine/lamivudine+nelfinavir
* This analysis includes all randomised patients through Week 24 and after that point is restricted to patients whose randomisation date allows for 36 or 48 weeks of follow-up. The number of patients at each point is indicated below the figure.
Once-Daily VIDEX (didanosine) Buffered Tablet Study Study AI454-148 was a randomised, open-label, multicenter study comparing treatment with VIDEX Chewable/Dispersible Buffered Tablets (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a mean CD4 cell count of 368 cells/mm3 (range 80 to 1568 cells/mm3) and a mean plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. The percentages of patients with HIV RNA <400 and <50 copies/mL and not meeting any criteria for treatment failure through 48 weeks are shown in Figure 2.
Percent of patients
0 8 16 24 32 40 48
Study Week
] < 50 c/mL
VIDEX Chewable/Dispersible Buffered Tablets+stavudine+nelfinavir (n=503)
zidovudine+lamivudine+nelfinavir (n=253)
*Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on their original study medication (except stavudine-zidovudine switches), and have not experienced an AIDS-defining event. For the differences between treatment groups at 48 weeks, p<0.05 by Cochran-Mantel-Haenszel test.
Double-combination: Didanosine alone at currently recommended doses, didanosine plus zidovudine (ZDV) and zalcitabine (ddC) plus ZDV were compared with ZDV alone in HIV- infected adults without AIDS and with CD4 cell counts of 200 - 500/mm3. ddC was administered at 0.75mg TID and ZDV was administered at 200 mg TID (ACTG 175). The risk of progressing to an AIDS-defining event or death was significantly lower for subjects initially assigned to didanosine (hazard ratio 0.69, p=0.019) or to didanosine plus ZDV (hazard ratio 0.64, p=0.005) as compared to those assigned to ZDV alone. The risk of dying was also lower in the two groups receiving didanosine alone or in combination with ZDV as compared to those assigned to ZDV alone. The risk of progression to the protocol defined endpoint (50% decline in CD4 cell count from baseline, progressing to an AIDS- defining event or death) was significantly reduced in all groups compared with ZDV alone. The risks of progression were similar for patients both with and without previous antiretroviral therapy.
The efficacy of Videx was demonstrated in a randomised, double-blind study, given on a BID schedule to zidovudine, given TID in 913 patients who had received prior zidovudine (
) with symptomatic HIV infection or AIDS who were treated for more than one year. Patients treated with Videx had a lower rate of HIV disease progression of death (32%) compared to those treated with zidovudine (41%); However survival rates were similar between the treatment groups.
Paediatric: Efficacy in paediatric patients was demonstrated in a randomised, double-blind, controlled study (ACTG 152) involving 831 patients treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), Videx (120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus Videx (90 mg/m2 q12h). Patients treated with Videx or Videx plus zidovudine had lower rates of HIV disease progression or death compared with those treated with zidovudine alone. Studies demonstrated that the clinical benefit of monotherapy with antiretrovirals, including Videx, was time limited.
Videx is indicated for use in adult and paediatric patients in the treatment of HIV infection in combination with other antiretroviral drugs (see Clinical Trials section of PHARMACOLOGY).
Videx is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulations.
In clinical trials, lower rates of pancreatitis were seen in patients with earlier stage HIV infection who were treated with currently recommended doses. The incidence of pancreatitis in clinical trials was dose-related. Pancreatitis is also a complication of HIV infection alone. When treatment is required with other drugs known to cause pancreatic toxicity (eg intravenous pentamidine) or known to increase exposure or activity of didanosine (eg hydroxyurea or allopurinol), suspension of Videx therapy is recommended. Allopurinol was observed to increase exposure to didanosine in renally impaired patients and healthy volunteers and may increase the risk of dose-related toxicities such as pancreatitis. It is recommended that these two drugs not be administered together. Videx should be used with caution in patients with risk factors for pancreatitis. For example, the following patients may be at increased risk for developing pancreatitis and should be followed closely for signs and symptoms of pancreatitis: patients with advanced HIV infection, patients with a history of pancreatitis, elderly patients, and patients with renal impairment if treated with unadjusted doses.
A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see
).
Hepatoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with antiretroviral agents in combination with hydroxyurea. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. Particular caution should be exercised when administering Videx to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Videx should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Patients who receive didanosine may develop toxic peripheral neuropathy and the frequency appears to be dose related. Patients with a history of peripheral neuropathy or those receiving Videx in combination with other neurotoxic drugs may be at increased risk for developing peripheral neuropathy (see ADVERSE EVENTS). These patients should be carefully observed. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine. Patients should be observed for the development of a neuropathy characterized by usually bilaterally symmetrical distal numbness, tingling, and pain in feet and, less frequently, hands. Symptoms of neuropathy which may be painful and eventually disabling, have been observed to resolve when didanosine dosing is suspended. Many patients tolerate a reduced dose of didanosine after resolution of symptoms. If facilities are available, neurophysiological assessment of peripheral nerve function should be considered. Neuropathy has occurred more frequently in patients with a history of neuropathy or neurotoxic drug therapy. Neuropathy has been reported rarely in the paediatric population treated with didanosine. However, as signs and symptoms of neuropathy are difficult to assess in children, physicians should be alerted to the possibility of this event.
Didanosine has been associated with hyperuricemia; treatment should be suspended if significant elevations in uric acid levels occur during the course of treatment with didanosine.
Liver failure of unknown etiology has occurred in less than 0.2% of patients receiving didanosine and has been fatal in some cases. Patients receiving didanosine should be closely observed for elevations in liver enzymes and didanosine should be suspended if enzymes rise to a clinically significant level above the ULN.
Paediatric patients receiving Videx have demonstrated retinal or optic nerve changes on rare occasions, particularly at doses above those recommended. There have also been reports of retinal depigmentation and optical neuritis in adults. Periodic retinal examinations should be considered for patients receiving Videx. Consideration should be given to modifying treatment based on the physician's assessment of benefit to risk. During clinical trials patients were monitored every 4 weeks. If increases in serum amylase, serum uric acid level or liver function tests occur or if the patient's condition warrants, more frequent monitoring should be considered. Insufficient clinical experience exists to recommend a dosing regimen in infants under 6 months of age. Patients receiving didanosine or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases. Clinical studies indicate that the risk of myelosuppression occurring during didanosine therapy was increased when the patient had pre-existing anaemia, leucopenia or thrombocytopenia. It is not always clear as to the extent that myelosuppression is HIV related. During clinical trials patients were monitored at 4 week intervals. If baseline haematology is unfavourable, more frequent monitoring should be considered.
Ingestion of didanosine with food reduces the amount of didanosine absorbed by as much as 50% and, as such, would be expected to result in significantly reduced beneficial activity of didanosine treatment. It is recommended that didanosine be administered on an empty stomach.
Videx Powder for Oral Solution (nonbuffered bulk, multiple dose formulation): Does not contain phenylalanine Videx EC capsules: Do not contain phenylalanine.
In adult patients with impaired renal function, the dose of Videx EC should be adjusted to compensate for the slower rate of elimination. For patients undergoing dialysis, the daily dose of Videx EC should be administered after dialysis. It is not necessary to administer a supplemental dose of Videx EC following haemodialysis (please refer to the Dosage and Administration section - Renal Impairment). 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 (please refer to the Dosage and Administration section - Renal Impairment).
The safety and efficacy of Videx have not been established in patients with significant underlying liver disorders. During combination antiretroviral therapy, patients with pre- existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered. The pharmacokinetics of didanosine were studied in haemophiliacs with hepatic impairment which required a documented history of periodic increases over the last 4 years in liver function enzymes (AST, ALT, GGT and alkaline phosphate) with at least one instance of two of these enzymes registering 3 x ULN within 6 months prior to screening. The pharmacokinetics of didanosine was not assessed in subjects with elevations in liver enzymes
5 x ULN.
No clinically significant changes in the pharmacokinetics of didanosine were observed among haemophiliac patients with chronic, persistent elevation in liver function enzymes, which may be indicative of impaired hepatic function; haemophiliac patients with normal or less severe increases in liver function enzymes; and non-haemophiliac patients with normal enzyme levels following a single IV or oral dose. The metabolism of didanosine may however be altered in patients with more severe or other forms of hepatic impairment; and adjustment of the dose should be considered (See DOSAGE AND ADMINISTRATION).
Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation and death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Common presenting features included elevated liver enzymes oesophageal varices, haematemesis, ascites, and splenomegaly. Patients receiving Videx 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 normalised ratio (INR) and ultrasonography should be considered. Videx should be discontinued in patients with evidence of non-cirrhotic portal hypertension.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Videx. In patents with severe immune deficiency at the time of institution of combination antiretroviral therapy, an inflammatory reaction to indolent or residual opportunistic pathogens may arise and cause serious clinical conditions or aggravation of symptoms. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia (PCP). 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.
Redistribution/accumulation of body fat (liodystrophy/lipoatrophy) including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy.
Patients receiving Videx may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases..
During clinical trials patients were monitored every 4 weeks. If increases in serum amylase, serum uric acid level or liver function tests occur or if the patient's condition warrants, more frequent monitoring should be considered. Clinical studies indicate that the risk of myelosuppression occurring during didanosine therapy was increased when the patient had pre-existing anaemia, leucopenia or thrombocytopenia. It is not always clear as to the extent that myelosuppression is HIV related. During clinical trials patients were monitored at 4 week intervals. If baseline haematology is unfavourable, more frequent monitoring should be considered.
Co-administration of Videx with drugs that are known to cause peripheral neuropathy or pancreatitis may increase the risk of these toxicities (see WARNINGS AND PRECAUTIONS: Pancreatitis and Peripheral Neuropathy).
When Videx tablets were coadministered with allopurinol in 2 patients with renal impairment (creatinine clearances 15-18 mL/min), the AUC of didanosine increased approximately 4-fold. In 14 healthy volunteers, the mean AUC of didanosine increased approximately 2-fold when Videx tablets were given with allopurinol. Thus the risk of dose- related toxicities, such as pancreatitis (see
), may be increased if Videx and allopurinol are administered together. It is recommended that these two drugs not be administered together.
Coadministration of methodone and didanosine may substantially reduce the effectiveness of didanosine. If co-administration is considered the therapeutic efficacy of didanosine requires careful assessment.
Coadministration of tenofovir disoproxil fumarate and didanosine may increase plasma concentrations of didanosine. Patients receiving these two drugs in combination should be considered for reduction of didanosine dose and should be carefully monitored for signs and symptoms of didanosine-related toxicity. Please also refer to the tenofovir prescribing information for further details on drug-interactions and precautions.
When Videx tablets were administered 1 hour before tenofovir disoproxil fumarate (both in the fasting state), the AUC of didanosine increased 44% relative to Videx alone in the fasted state. When Videx EC was administered (in the fasting state) 2 hours before tenofovir disoproxil fumarate with a light meal, the AUC of didanosine was increased 48% relative to Videx EC alone in the fasted state. When Videx EC was administered together with tenofovir disoproxil fumarate and a light meal, the AUC of didanosine increased 60% relative to Videx EC alone in the fasted state.
When didanosine was co-administered with delavirdine there was a decrease of approximately 20% in the AUC for both didanosine and delavirdine, relative to when administration was separated by at least 1 hour. Administration of didanosine and delavirdine should be separated by at least 1 hour.
: Exposure to didanosine or its active metabolite (dideoxyadenosine 5'- triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities. Co-administration of didanosine and ribavirin is not recommended. There have been reports of fatal hepatic failure, as well as peripheral
neuropathy, pancreatitis and symptomatic hyperlactactemia/lactic acidosis.
Indinavir and Videx tablets (or the powder formulation) should be administered at least one hour apart on an empty stomach. Indinavir may need an acidic gastric pH for optimum absorption whereas didanosine is degraded by acid; Videx tablets (or the powder formulation) are buffered to increase the gastric pH.
Specific drug interaction studies have been conducted between Videx tablet formulations and zidovudine, stavudine, ranitidine, loperamide, metoclopramide, foscarnet, trimethoprim, sulfamethoxazole, dapsone and rifabutin without evidence of interaction. Specific drug interaction studies have been conducted between Videx EC capsules and ciprofloxacin, indinavir and ketoconazole without evidence of interaction. Co-administration of Videx with drugs that are known to cause peripheral neuropathy or pancreatitis may increase the risk of these toxicities. Patients who receive these drugs should be carefully observed. Neuropathy has occurred more frequently in patients with a history of neuropathy or neurotoxic drug therapy and these patients may be at increased risk of neuropathy during Videx therapy (see Adverse Events).
Videx EC capsules may be given simultaneously with agents such as ketoconcazole and itraconazole, since gastric acidity is not affected by this didanosine formulation. Videx buffered formulations should be administered at least two hours after drugs such as ketoconazole or itraconazole.
At an oral dose of 1000 mg of ganciclovir every 8 hours and didanosine 200 mg every 12 hours, the steady state didanosine AUC0-12 increased 111 +/- 114% (range: 10% to 493%) when didanosine was administered either 2 hours prior to or concurrent with administration of ganciclovir (n=12 patients, 23 observations). A decrease in steady state ganciclovir AUC of 21 +/- 17% (range: -44% to 5%) was observed when didanosine was administered 2 hours prior to administration of ganciclovir, but the ganciclovir AUC was not effected by the presence of didanosine when the two drugs were administered simultaneously (n=12). As with other products containing aluminium antacid components, Videx Paediatric Powder for Oral Solution that has been constituted with water and mixed with antacid containing aluminium components should not be taken with a prescription antibiotic containing any form of tetracycline. Also, plasma concentrations of some quinolone antibiotics may be decreased by administration with antacids contained in Videx tablets. It is recommended that drugs which may interact with antacids should not be administered within 2 hours of taking Videx Paediatric Powder for Oral Solution.
Lifetime carcinogenicity studies were performed in mice and rats for 22 and 24 months, respectively. Mice were administered dietary didanosine 120, 800 or 1200mg/kg/day. Due to toxicity, the mid- and high-doses were lowered to 300 and 600 mg/kg/day, respectively, in week 20 in females and in week 36 in males, and were further reduced to 210 mg/kg/day in mid- and high-dose females in week 36. At the maximum tolerated doses of 120mg/kg/day in females and 300 mg/kg/day in males, systemic exposures were approximately 1.1 and 2.7 times, respectively, the clinical exposure (AUC0-24h). Rats were administered dietary didanosine 100, 250 or 1000 mg/kg/day. The high-dose was reduced to 500 mg/kg/day after 18 months, due to toxicity. Systemic exposures in the 18th month at the respective doses were approximately 0.59, 1.2 and 5.9 times the clinical exposure (AUC0-24h). There was no evidence of carcinogenicity in either species at the maximally tolerated doses. No evidence of mutagenicity (with or without metabolic activation) was observed in Ames Salmonella mutagenicity assays or in a mutageniticy assay conducted with Escherichia coli tester strain WP2 uvrA where only a slight increase in revertants was observed with Videx. In a mammalian cell gene mutation assay conducted in L5178Y/TK +/- mouse lymphoma cells, didanosine was weakly positive both in the absence and presence of metabolic activation at concentrations of approximately 2000 g/mL and above. In an in vitro cytogenic study performed in cultured human peripheral lymphocytes, high concentrations of didanosine (>500 g/mL) elevated the frequency of cells bearing chromosome aberrations. Another in vitro mammalian cell chromosome aberration study using Chinese Hamster Lung cells revealed that didanosine produces chromosome aberrations at >500 g/mL after 48 hours of exposure. However, no significant elevations in the frequency of cells with chromosome aberrations were seen at didanosine concentrations up to 250 g/mL. Similar chromosomal aberation effects were induced by the natural nucleoside of didanosine (2'- deoxyinosine), suggesting that these effects of didanosine were not due to a direct genotoxic interaction. In a BALB/c 3T3 in vitro transformation assay, didanosine was considered positive only at concentrations of 3000 g/mL and above, whereas deoxyinosine induced a positive response in this assay at 1000 g/mL and above. No evidence of genotoxicity was observed in rat and mouse micronucleus assays. The rats received oral didanosine (up to 100mg/kg/day) for 7 days. The mice received oral didanosine (up to 1000mg/kg/day) for 4 weeks or intravenous didanosine (up to 250mg/kg/day) for 4 days. The results from the genotoxicity studies suggest that didanosine is not mutagenic at biologically and pharmacologically relevant doses. At significantly elevated doses in vitro, the genotoxic effects of didanosine are similar in magnitude to those seen with natural DNA nucleosides.
A reproductive toxicity study in rats administered didanosine 100, 300 or 1000 mg/kg/day by gavage showed no impairment of fertility, but at the high dose, maternal food intake and pup bodyweights were slightly reduced in mid- and late lactation, but recovered post-weaning. Rat plasma didanosine levels at the high dose were of the same order or slightly higher than values obtained in clinical use.
Pregnancy Category B2
There are no adequate and well controlled studies of didanosine in pregnant women. Videx should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is not known if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in non-pregnant individuals receiving nucleoside analogues (see WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefits outweigh the potential risk. Health care providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Teratology studies in pregnant rats and rabbits showed no evidence of embryotoxic or teratogenic activity at didanosine gavage doses up to 1000 and 600mg/kg/day, respectively. The low level of toxicity seen in these studies may be due to the apparent low systemic exposure of the animals to the drug. Plasma levels of didanosine in rats at doses of 1000mg/kg/day were of the same order or slightly higher, while in rabbits at doses of 600mg/kg/day were 10-fold higher than values obtained in clinical use. A gavage study in pregnant rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response.
It is not known whether didanosine is excreted in human milk. Animal studies have shown the transfer of didanosine and/or its metabolites to lactating rat milk at a concentration which suggests active secretion. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from didanosine in nursing infants, mothers should be instructed to discontinue nursing if they are receiving didanosine.
A serious toxicity of Videx is pancreatitis. Pancreatitis resulting in death has been observed in patients who received Videx alone or in combination regiments (including combinations that contain stavudine) in controlled clinical trials and in spontaneous reports (see WARNINGS AND PRECAUTIONS).
Patients treated with Videx in combination with Zerit (stavudine), with or without hydroxyurea may be at increased risk for pancreatitis.
Other important toxicities include lactic acidosis and severe hepatomegaly with steatosis, retinal changes, optical neuritis and peripheral neuropathy (see WARNINGS AND PRECAUTIONS). When Videx is used in combination with other agents with similar toxicities, the incidences of these toxicities may be higher than when Videx is used alone. Thus patients treated with combination regimens including stavudine may be at risk for liver function abnormalities and peripheral neuropathy (see WARNINGS AND PRECAUTIONS).
Studies of VIDEX EC and a buffered didanosine formulation yielded comparable safety profiles for both formulations. Selected clinical adverse events that occurred in clinical studies of didanosine dosed once daily in combination with other antiretroviral agents are provided in Table 1.
| Table 1 Selected Clinical Adverse Events from Combination Studies of Didanosine Dosed Once Daily | ||||
| Percent of Patients a | ||||
| AI454-152 b | AI454-148 c | |||
| VIDEX EC+ stavudine + nelfinavir | zidovudine/ lamivudine d + nelfinavir | VIDEX Buffered Tablet+stavudine+ nelfinavir | zidovudine+ lamivudine + nelfinavir | |
| Adverse Events | n=255 | n=250 | n=482 | n=248 |
| Diarrhoea | 54 | 56 | 70 | 60 |
| Nausea | 21 | 35 | 28 | 40 |
| Headache | 20 | 16 | 21 | 30 |
| Peripheral Neurologic Symptoms/Neuropathy | 20 | 8 | 26 | 6 |
| Vomiting | 13 | 18 | 12 | 14 |
| Rash | 10 | 10 | 13 | 16 |
| Pancreatitis (see below) | <1 | * | 1 | * |
| a Percentages based on treated patients. b Median duration of treatment 43 weeks in the VIDEX EC+stavudine+nelfinavir group and 39 weeks in the zidovudine/lamivudine+nelfinavir group. c Median duration of treatment 48 weeks. d Zidovudine/lamivudine combination tablet. * This event was not observed in this study arm. | ||||
Selected clinical adverse events that occurred in adult patients in monotherapy studies (with Videx tablets) are provided in Table 2
| Table 2 Selected Clinical Adverse Events from Monotherapy Studies | ||
| Percent of Patients a | ||
| ACTG 116B/117 | ||
| VIDEX | zidovudine | |
| Adverse Events | n=298 | n=304 |
| Diarrhoea | 28 | 21 |
| Peripheral Neurologic Symptoms/Neuropathy | 20 | 12 |
| Rash/Pruritis | 9 | 5 |
| Abdominal pain | 7 | 8 |
| Pancreatitis (see below) | 6 | 2 |
| a Percentages based on treated subjects. b Median duration of treatment 48 weeks. | ||
In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received VIDEX EC plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz (see WARNINGS). The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose.
Selected laboratory abnormalities that occurred in clinical studies of didanosine dosed once daily in combination with other antiretroviral agents are shown in Table 3.
| Table 3 Selected Laboratory Abnormalities from Combination Studies of Didanosine Dosed Once Daily | ||||||||
| Percent of Patients a | ||||||||
| AI454-152 b | AI454-148 c | |||||||
| VIDEX EC+ stavudine +nelfinavir n=255 | zidovudine/ lamivudine d +nelfinavir n=250 | VIDEX Buffered Tablet+ stavudine +nelfinavir n=482 | zidovudine+ lamivudine +nelfinavir n=248 | |||||
| Parameter | Grades 3-4 e | All Grades | Grades 3-4 e | All Grades | Grades 3-4 e | All Grades | Grades 3-4 e | All Grades |
| AST | 4 | 40 | 4 | 17 | 3 | 42 | 2 | 23 |
| ALT | 4 | 39 | 4 | 20 | 3 | 37 | 3 | 24 |
| Lipase | 3 | 18 | <1 | 8 | 7 | 17 | 2 | 11 |
| Bilirubin | <1 | 7 | <1 | 3 | <1 | 7 | <1 | 3 |
| a Percentages based on treated patients. b Median duration of treatment 43 weeks in the VIDEX EC+stavudine+nelfinavir group and 39 weeks in the zidovudine/lamivudine+nelfinavir group. c Median duration of treatment 48 weeks. d Zidovudine/lamivudine combination tablet. e >5 x ULN for SGOT and SGPT, 2.1 x ULN for lipase, and 2.6 x ULN for bilirubin (ULN = upper limit of normal). | ||||||||
Selected laboratory abnormalities that occurred in clinical studies of didanosine in monotherapy (with Videx tablets) are shown in Table 4.
| Table 4 Selected Laboratory Abnormalities from Monotherapy Studies | ||
| Percent of Patients | ||
| ACTG 116B/117 | ||
| VIDEX zidovudine n=298 n=304 | ||
| Parameter | ||
| AST (>5 x ULN) 7 | 6 | |
| ALT (>5 x ULN) 6 | 6 | |
| Alkaline phosphatase (>5 x ULN) 1 | 1 | |
| Amylase ( 1.4 x ULN) 1 | 5 | 5 |
| Uric acid (>12 mg/dL) 2 | 1 | |
| ULN = upper limit of normal | ||
Observed During Clinical Practice
. The following events have been identified during post approval use of Videx. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, or causal connection to didanosine, or a combination of these factors.
Body as a Whole
- alopecia, anaphylactoid reaction, asthenia, chills/fever and pain.
Digestive Disorders
- anorexia, dyspepsia and flatulence.
Exocrine Gland Disorders - pancreatitis (including fatal cases - see WARNINGS AND PRECAUTIONS), sialadenitis, parotid gland enlargement, dry mouth and dry eyes.
Haematological Disorders
- anaemia, granulocytopenia, leukopenia and thrombocytopenia.
Liver - lactic acidosis and hepatic steatosis (see WARNINGS AND PRECAUTIONS), hepatitis and liver failure.
Metabolic Disorders
- diabetes mellitus, elevated serum alkaline phosphatase level, elevated serum amylase level, hypoglycemia and hyperglycemia.
Musculoskeletal Disorders
- myalgia (with or without increases in creatinine phosphokinase), rhabdomyolysis including acute renal failure and haemodialysis, arthralgia and myopathy.
Ophthalmologic Disorders - retinal depigmentation and optic neuritis (see WARNINGS AND PRECAUTIONS).
Non-cirrhotic portal hypertension
(see WARNINGS AND PRECAUTIONS)
Paediatric Patients:
Adverse events reported to occur in the paediatric patients in the ACTG 152 trial were generally similar to those reported in adults.
In paediatric phase I studies, pancreatitis occurred in 2 of 60 (3 percent) patients treated at entry doses below 300 mg/m2/day and in 5 of 38 (13 percent) patients treated at higher doses. Retinal changes and optic neuritis have been reported in several paediatric patients who received didanosine at and above the recommended dose. Serious laboratory abnormalities experienced by the paediatric patients in the ACTG 152 clinical trial are listed in Table 5.
| Table 5: Paediatric Patient Serious Laboratory Abnormalities in ACTG 152 (Cumulative Incidences) | |||
| Percent of Patients | |||
| Laboratory Test | VIDEX | VIDEX + zidovudine | zidovudine |
| (Seriously Abnormal Level) | N = 281 | N = 274 | N = 276 |
| Haemoglobin (<7.5 g/dL) | 5 | 7 | 10 |
| Leucopenia (<2000/ L) | <1 | <1 | 1 |
| Granulocytopenia (<500/ L) | 11 | 16 | 27 |
| Thrombocytopenia (<50,000/ L) | 6 | 7 | 7 |
| AST ( 5 x ULN) | 14 | 10 | 16 |
| ALT ( 10 x ULN) | 5 | 2 | 7 |
| Alkaline Phosphatase ( 2 x ULN) | 7 | 9 | 10 |
| Bilirubin ( 2.6 x ULN) | 6 | 3 | 4 |
| Amylase ( 3.1 x ULN) | 5 | 6 | 7 |
| Creatine Kinase ( 5.1 x ULN) | 6 | 8 | 8 |
| Uric Acid ( 3.5 x ULN) | <1 | <1 | <1 |
Dosage: Adults
Videx EC Capsules
The recommended daily dose is dependent on body weight and is administered as one capsule given on a once daily schedule as outlined in Table 6.
Table 6: | |
|---|---|
| Patient Baseline Weight | VIDEX EC capsules |
| < 60kg | 250mg OD |
| 60kg | 400mg OD |
Dosage: Children
Videx Powder for Oral Solution
The range of doses shown to be safe and effective in children >6 months of age are from 100 to 300mg/m2 per day.
That is at least 30 minutes before or 2 hours after eating. The recommended dose of VIDEX Powder for Oral Solution in paediatric patients is
There are no data on once-daily dosing of Videx in paediatric patients
Dose Adjustment
Elevations of serum amylase above 2.0 x ULN should prompt dose suspension 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 should dosing be resumed. Many patients who have presented with symptoms of neuropathy will tolerate a reduced dose of didanosine after resolution of these symptoms upon drug discontinuation.
In adult patients with impaired renal function, the dose of Videx EC should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of Videx EC in adult patients with renal insufficiency are presented in Table 7.
| Creatinine Clearance (mL/min) | Dosage (mg) | |
| At least 60kg | Less than 60kg | |
| at least 60 | 400 once daily | 250 once daily |
| 30-59 | 200 once daily | 125 once daily |
| 10-29 | 125 once daily | 125 once daily |
| Less than 10 | 125 once daily | b |
a
Based on studies using buffered formulation of didanosine
b Not suitable for use in patients less than 60kg with CLcr less then 10mL/min.
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.
: There are insufficient data to recommend a specific dose adjustment of Videx in patients with hepatic impairment, but a reduction in the dose in these patients should be considered (see WARNINGS AND PRECAUTIONS).
If symptoms of peripheral neuropathy occur (see ADVERSE EVENTS), Videx therapy should be suspended until resolution of symptoms After resolution of these symptoms, patients may tolerate a reduced dose of Videx.
Studies evaluating the stability of the beadlets outside the capsules have not been completed. The recommended daily dose is dependent on body weight and is usually administered as one capsule.
Method of Preparation:
Prior to dispensing, the pharmacist must constitute the dry powder with Purified Water, USP to an initial concentration of 20mg/mL and immediately mix the resulting solution with antacid to a final concentration of 10mg/mL or 5mg/mL as follows: For a 20mg/mL Initial Concentration Constitute the product to 20mg/mL by adding 100 mL of Purified Water, USP, to the 2 g of didanosine dry powder, in the product bottle. For a 10mg/mL Final Concentration
Immediately mix one part of the 20mg/mL constituted solution with one part of Mylanta II Liquid for a final dispensing concentration of 10mg didanosine per mL. For patient home use, the constituted-product/antacid mixture should be dispensed in appropriately sized, flint-glass bottles with child-resistant closures. This didanosine solution/antacid mixture is stable for 30 days under refrigeration, 20- 80C.
Instruct the patient to shake the didanosine/antacid mixture thoroughly prior to use and to store the mixture in a tightly closed container in the refrigerator, 20-80C for 30 days.
For a 5mg/mL Final Concentration
Immediately mix one part of the 20mg/mL constituted solution with three parts of Mylanta II Liquid for a final dispensing concentration of 5mg didanosine per mL. For patient home use, the constituted-product/antacid mixture should be dispensed in appropriately sized, flint-glass bottles with child-resistant closures. This didanosine solution/antacid mixture is stable for 30 days under refrigeration, 20- 80C.
Instruct the patient to shake the didanosine/antacid mixture thoroughly prior to use and to store the mixture in a tightly closed container in the refrigerator, 20- 80C up to 30 days.
Information for Patients
Didanosine is not a cure for AIDS-HIV infection, and patients may continue to acquire illnesses associated with AIDS or AIDS Related Complex, including opportunistic infections. Therefore, patients should be advised to seek medical care for any significant change in their health status. Patients should be informed that the major dose-limiting toxicities of didanosine are peripheral neuropathy and pancreatitis and that these events occur with greatest frequency in patients with a history of these events. They should be told that dose modifications and/or discontinuation of didanosine may be required if toxicity develops. They should be cautioned about the use of other medications that may exacerbate the toxicity of didanosine, including alcohol. Patients should be told that the long-term effects of didanosine are unknown at this time. Patients should be advised that didanosine therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.
There is no known antidote for didanosine overdosage. Experience in the Phase I studies in which didanosine was initially administered at doses ten times the recommended doses indicates that the anticipated complications of chronic overdosage would include pancreatitis, peripheral neuropathy, diarrhoea, hyperuricemia or, possibly 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 20-30% of the amount present in the body at the start of dialysis). In case of overdose, immediately contact the Poisons Information Centre on 13 11 26 for advice.
are white, opaque, imprinted capsules, supplied in Bottles or in Blister Packs
of 30 capsules.
| Strength | Capsule Imprint | Imprint colour |
| 125mg | BMS 125mg 6671 | Tan |
| 200mg | BMS 200mg 6672 | Green |
| 250mg | BMS 250mg 6673 | Blue |
| 400mg | BMS 400mg 6674 | Red |
Videx EC should be in bottles stored below 25 degrees Celsius.
is supplied in 120mL glass bottles containing 2g of didanosine.
The bottles of the dry product should be stored below 300C. The constituted Videx solution/antacid mixture may be stored up to thirty days in a refrigerator, 20- 80C. Discard any unused portion after thirty days.
Bristol-Myers Squibb Company, USA.
Bristol-Myers Squibb Australia Pty Ltd 4 Nexus Court, Mulgrave, Victoria 3170, Australia.
Videx EC 125mg capsule (Bottle) AUST R 78351 Videx EC 200mg capsule (Bottle) AUST R 78353 Videx EC 250mg capsule (Bottle) AUST R 78355 Videx EC 400mg capsule (Bottle) AUST R 78357 Videx Paediatric Powder 2g AUST R 34306 (not marketed)
8 May 2001
: 13 September 2013