|
Product
Antiretroviral products (Dinex EC )
|
Antiretroviral products (Dinex EC)
|
|
| |
|
Dinex EC
Didanosine delayed-release Capsules Enteric-coated beadlets
COMPOSITION
DINEX EC 250
Each capsule contains:
Didanosine (as enteric coated beadlets) 250 mg
DINEX EC 400
Each capsule contains:
Didanosine (as enteric coated beadlets) 400 mg
DOSAGE FORM
Oral capsule
PHARMACOLOGY
Pharmacodynamics
Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3`-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5`-triphosphate.Dideoxyadenosine 5`-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5`-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation.
|
Pharmacokinetics
The pharmacokinetic parameters of didanosine in HIV-infected adult and pediatric patients are summarized in Table 1, by weight ranges that correspond to recommended doses (Table 1). Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. In adults, the average oral bioavailability following single oral dosing with a buffered formulation is 42 (±12)%. After oral administration, the urinary recovery of didanosine is approximately 18 (±8)% of the dose. The CSF-plasma ratio following IV administration is 21 (±0.03)%. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (less than 5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.
Effect of Food on Absorption of Didanosine
In the presence of food, the C max and AUC for didanosine were reduced by approximately 46% and 19%, respectively, compared to the fasting state [ see DOSAGE AND ADMINISTRATION ]. DINEX-EC should be taken on an empty stomach.
Special Populations
Renal Insufficiency: Data from two studies using a buffered formulation of didanosine indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis.
Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non-HIV infected subjects with moderate (n=8) to severe (n=4) hepatic impairment (Child-Pugh Class B or C). Mean AUC and C max values following a single 400 mg dose of didanosine were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because a similar range and distribution of AUC and C max values was observed for subjects with hepatic impairment and matched healthy controls.
Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and HIV-infected pediatric patients from birth to adulthood. A population pharmacokinetic analysis was conducted on pooled didanosine plasma concentration data from 9 clinical trials in 106 pediatric (neonate to 18 years of age) and 45 adult patients (greater than 18 years of age). Results showed that body weight is the primary factor associated with oral clearance. Based on the data analyzed, dosing schedule (once versus twice daily) and formulation (powder for oral solution, tablet, and delayed-release capsule) did not have an effect on oral clearance. Didanosine exposure similar to that at recommended adult doses can be achieved in pediatric patients with a weight-based dosing scheme [ see DOSAGE AND ADMINISTRATION ].
Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age.
Gender: The effects of gender on didanosine pharmacokinetics have not been studied.
INDICATIONS
DINEX EC in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection.
DOSAGE AND ADMINISTRATION
DINEX-EC (didanosine) should be administered on an empty stomach. DINEX-EC Delayed-Release Capsules should be swallowed intact.
Recommended Dosage (Adult and Pediatric Patients)
The recommended total daily dose is based on body weight and is administered as one capsule given on a once-daily schedule as outlined in Table 3.
The recommended total daily dose to be administered once daily to pediatric patients weighing at least 20 kg who can swallow capsules is based on body weight (kg), consistent with the recommended adult dosing guidelines (see Table 3).
Table 3: Recommended Dosage (Adult and Pediatric Patients)
| Body Weight |
Dose |
| 20kg to less than 25kg |
200 mg once daily |
| 20kg to less than 60kg |
250 mg once daily |
| at least 60kg |
400 mg once daily |
Renal impairment:
Adult Patients
In adult patients with impaired renal function, the dose of DINEX-EC should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of DINEX-EC in adult patients with renal insufficiency are presented in Table4.
Table 4 Recommended Dosage in Patients with Renal Impairment by Body Weight a
| Creatinine Clearance(mL/min) |
Dosage(mg)
|
| at least 60kg | at least 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 a buffered formulation of didanosie.
bNot suitable for use in patients less than 60 kg with CLcr less than 10 mL/min.An alternate formulation of didanosine should be used.
Pediatric Patients
Urinary excretion is also a major route of elimination of didanosine in pediatric patients, therefore the clearance of didanosine may be altered in pediatric patients with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of DINEX- EC in this patient population, a reduction in the dose should be considered (see Table 4).
Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis
For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance of less than 10 mL/min, shown in Table 4. It is not necessary to administer a supplemental dose of didanosine following hemodialysis.
Dose adjustment:
Pancreatitis
Clinical and laboratory signs suggestive of pancreatitis showed prompt dose suspension and careful evaluation of the possibility of pancreatitis. DINEX EC use should be discontinued in patients with confirmed pancreatitis. ( See WARNINGS AND PRECAUTIONS: DRUG INTERACTIONS )
Peripheral neuropathy
Based on data with buffered didanosine formulations, patients with symptoms of peripheral neuropathy may tolerate a reduced dose of didanosine-delayed release, after resolution of the symptoms of peripheral neuropathy upon drug interruption.If neuropathy recurs after resumption of the drug, permanent discontinuation should be considered.
Concomitant therapy with Tenofovir disoproxil fumarate .
In patients who are also taking tenofovir disoproxil fumarate, a dose reduction of DINEX EC to 250 mg (adults weighing ³ 60 kg with creatinine clearance ³ 60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ³ 60 mL/min) once daily taken together with tenofovir and a light meal ( £ 400 kcalories, £ 20% fat) or in the fasted state is recommended. The appropriate dose of DINEX EC co-administered with tenofovir in patients with creatinine clearance <60 mL/min has not been established.[ See WARNINGS AND PRECAUTIONS : DRUG INTERACTIONS ]
Hepatic Impairment: No dose adjustment is required in patients with hepatic impairment [ see WARNINGS AND PRECAUTIONS]
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
General
Patients with Renal Impairment: Patients with renal impairment (creatinine clearance < 60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance. A dose reduction is recommended in these patients.
Hyperuricemia : Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fall.
Dosing
DINEX EC should be administered once daily on an empty stomach.
Pancreatitis
Fatal and non-fatal pancreatitis have occurred during therapy with didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Dinex-ec should be suspended in patients with signs or symptoms of pancreatitis. Patients treated with dinex-ec in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitits.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of didanosine therapy is recommended. In patients with risk factors for pancreatitis, DINEX EC should be used with extreme caution and only if clearly indicated.Patients with advanced HIV infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. [ See UNDESIRABLE EFFECTS ]
Lactic acidosis / Severe hepatomegaly with steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant 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 WARNINGS AND PRECAUTIONS: Pregnancy ).
Particular caution should be exercised when administering didanosine 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 DINEX EC should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Retinal changes and optic neuritis
Retinal changes and optic neuritis have been reported in adult and pediatric patients taking didanosine. Periodic retinal examinations should be considered for patients receiving DINEX EC (see UNDESIRABLE EFFECTS ).
Hepatic Toxicity
The safety and efficacy of didanosine have not been established in HIV-infected patients with significant underlying liver disease.During combination antiretroviral therapy, patients with preexisting 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 must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents.Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine and stavudine. This combination should be avoided.
Peripheral neuropathy
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving didanosine therapy.Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine. ( see UNDESIRABLE EFFECTS ).
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including DINEX EC . During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Fat Redistribution
Redistribution/accumulation of body fat 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. The mechanism and longterm consequences of these events are currently unknown. A causal relationship has not been established.
Hyperuricemia
Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail
Pregnancy
Pregnancy Category B:
Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. These rats showed reduced food intake and body weight gains but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation. A study in 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.
There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine 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 unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues [ see WARNINGS AND PRECAUTIONS ]. 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. Healthcare providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Lactation
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving didanosine .
Pediatric Use
Use of didanosine in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of didanosine in adult and pediatric patients [ see DOSAGE AND ADMINISTRATION and UNDESIRABLE EFFECTS]
Additional pharmacokinetic studies in pediatric patients support use of didanosine in pediatric patients who weigh at least 20 kg.
Geriatric Use
Clinical studies of didanosine, including those for didanosine enteric coated, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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.
Renal Impairment
Patients with renal impairment (creatinine clearance of less than 60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance. A dose reduction is recommended for these patients [ see Dosage and Administration ].
UNDESIRABLE EFFECTS
The following adverse reactions are discussed in greater detail in other sections:
• Pancreatitis [ see Boxed Warning, Warnings and Precautions ]
• Lactic acidosis/severe hepatomegaly with steatosis [ see Boxed Warning, Warnings and Precautions ]
• Hepatic toxicity [ see Warnings and Precautions ]
• Peripheral neuropathy [ see Warnings and Precautions ]
• Retinal changes and optic neuritis [ see Warnings and Precautions ]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Pediatric Patients
In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with didanosine. Adverse reactions and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults.
In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m 2 /day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m 2 every 12 hours and in less than 1% of the 274 pediatric patients who received didanosine 90 mg/m 2 every 12 hours in combination with zidovudine.
Retinal changes and optic neuritis have been reported in pediatric patients.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of didanosine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to didanosine, or a combination of these factors.
Blood and Lymphatic System Disorders - anemia, leukopenia, and thrombocytopenia.
Body as a Whole - abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat [ see WARNINGS AND PRECAUTIONS ].
Digestive Disorders - anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders - pancreatitis (including fatal cases) [ see WARNINGS AND PRECAUTIONS ], sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hepatobiliary Disorders - symptomatic hyperlactatemia/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, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia, and hyperglycemia.
Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.
Ophthalmologic Disorders - retinal depigmentation and optic neuritis [ see WARNINGS AND PRECAUTIONS ].
Use with Stavudine- and Hydroxyurea-Based Regimens
When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with didanosine enteric coated in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy. The combination of DINEX-EC and hydroxyurea, with or without stavudine, should be avoided [ see WARNINGS AND PRECAUTIONS ].
OVERDOSAGE
There is no known antidote for didanosine overdosage.In phase 1 studies, in which buffered formulations of didanosine were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricaemia and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis.
PACKAGING INFORMATION
DINEX EC 250: Container of 30 capsules
DINEX EC 400: Container of 30 capsules
|
|
