Ciproxyl may be available in the countries listed below.
Ciprofloxacin hydrochloride (a derivative of Ciprofloxacin) is reported as an ingredient of Ciproxyl in the following countries:
International Drug Name Search
Chlor-Tetracyclin-Spray Stricker may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Chlortetracycline hydrochloride (a derivative of Chlortetracycline) is reported as an ingredient of Chlor-Tetracyclin-Spray Stricker in the following countries:
International Drug Name Search
Tetrax may be available in the countries listed below.
Tetracycline hydrochloride (a derivative of Tetracycline) is reported as an ingredient of Tetrax in the following countries:
International Drug Name Search
Citalopram Sumol may be available in the countries listed below.
Citalopram hydrobromide (a derivative of Citalopram) is reported as an ingredient of Citalopram Sumol in the following countries:
International Drug Name Search
Balsam Peru is an effective capillary bed stimulant used to increase circulation in the wound area. Also, Balsam Peru has a mild bactericidal action. Castor Oil is used to improve epithelialization by reducing premature epithelial desiccation and cornification. Also, it can act as a protective covering and aids in the reduction of pain. Trypsin is intended for debridement of eschar and other necrotic tissue. It appears that in many instances removal of wound debris strengthens humoral defense mechanisms sufficiently to retard proliferation of local pathogens.
To promote healing and the treatment of decubitus ulcers, varicose ulcers and dehiscent wounds.
Do not apply to fresh arterial clots. Avoid contact with eyes. Keep out of reach of children. Use only as directed. When applied to a sensitive area, a temporary stinging sensation may be noted.
Remove Safety Seal under cap. Apply a thin film of OPTASETM Gel a minimum of twice daily or as often as necessary. The wound may be left unbandaged or appropriate dressing applied. To remove, wash gently with appropriate cleanser.
OPTASETM Gel is supplied in 95g bottles (NDC# 16781-116-95) and 6g tubes (NDC# 16781-116-06). Store OPTASETM Gel between 59-86ºF (15-30ºC). Avoid freezing.
FOR EXTERNAL USE ONLY
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Optase Bottle Front Label
NDC 16781-116-95
Rx Only
WOUND CARE GEL
Optase™
FOR EXTERNAL USE ONLY
NET WT. 95g PATENT PENDING
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Optase 10 Tube Label
NDC 16781-116-06
Rx Only
Net Wt. 6g
WOUND CARE GEL
Optase®
Trypsin USP, Balsam Peru, Castor Oil USP
| OPTASE trypsin,castor oil,balsam, peru gel | ||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| Unapproved drug other | 04/01/2006 | 12/31/2011 | |
| Labeler - Onset Dermatologics LLC (793223707) |
| Registrant - Onset Dermatologics LLC (964275155) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Onset Dermatologics LLC | 793223707 | Manufacture | |
Acébutolol Almus may be available in the countries listed below.
Acebutolol hydrochloride (a derivative of Acebutolol) is reported as an ingredient of Acébutolol Almus in the following countries:
International Drug Name Search
Bricanyl Depot may be available in the countries listed below.
Terbutaline sulfate (a derivative of Terbutaline) is reported as an ingredient of Bricanyl Depot in the following countries:
International Drug Name Search
Collirio Alfa may be available in the countries listed below.
Naphazoline nitrate (a derivative of Naphazoline) is reported as an ingredient of Collirio Alfa in the following countries:
International Drug Name Search
Hikamilon may be available in the countries listed below.
Hyaluronic Acid sodium salt (a derivative of Hyaluronic Acid) is reported as an ingredient of Hikamilon in the following countries:
International Drug Name Search
Renator may be available in the countries listed below.
Ciprofloxacin is reported as an ingredient of Renator in the following countries:
International Drug Name Search
Trimetazidina Jaba may be available in the countries listed below.
Trimetazidine dihydrochloride (a derivative of Trimetazidine) is reported as an ingredient of Trimetazidina Jaba in the following countries:
International Drug Name Search
Fatal and nonfatal pancreatitis has occurred during therapy with Didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Didanosine delayed-release capsules should be suspended in patients with suspected pancreatitis and discontinued in patients with confirmed pancreatitis [see Warnings and Precautions (5.1)].
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. 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 (5.2)].
Didanosine delayed-release capsules, also known as ddI, in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14)].
Didanosine delayed-release capsules should be administered on an empty stomach. Didanosine delayed-release capsules should be swallowed intact.
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 1.
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 1). Please consult the complete prescribing information for Didanosine Pediatric Powder for Oral Solution for dosage and administration of Didanosine to pediatric patients weighing less than 20 kg or who can not swallow capsules.
| Body Weight | Dose |
| 20 kg to less than 25 kg | 200 mg once daily |
| 25 kg to less than 60 kg | 250 mg once daily |
| at least 60 kg | 400 mg once daily |
Dosing recommendations for Didanosine delayed-release capsules are different for patients with renal impairment.
Adult Patients
In adult patients with impaired renal function, the dose of Didanosine delayed-release capsules should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of Didanosine delayed-release capsules in adult patients with renal insufficiency are presented in Table 2.
| ||
Creatinine Clearance (mL/min) | Dosage (mg) | |
| at least 60 kg | less than 60 kg | |
| at least 60 | 400 once daily | 250 once daily |
| 30 to 59 | 200 once daily | 125 once daily |
| 10 to 29 | 125 once daily | 125 once daily |
| less than 10 | 125 once daily | † |
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 Didanosine delayed-release capsules in this patient population, a reduction in the dose should be considered (see Table 2).
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 2. It is not necessary to administer a supplemental dose of Didanosine following hemodialysis.
Concomitant Therapy with Tenofovir Disoproxil Fumarate
In patients who are also taking tenofovir disoproxil fumarate, a dose reduction of Didanosine delayed-release capsules to 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) or 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less, 20% fat or less) or in the fasted state is recommended. The appropriate dose of Didanosine delayed-release capsules coadministered with tenofovir disoproxil fumarate in patients with creatinine clearance of less than 60 mL/min has not been established [see Drug Interactions (7) and Clinical Pharmacology(12.3)].
Hepatic Impairment
No dose adjustment is required in patients with hepatic impairment [see Warnings andPrecautions (5.3) and Clinical Pharmacology (12.3)].
Didanosine Delayed-Release Capsules are available as:
200 mg: Two-piece hard gelatin capsule with green opaque cap and white opaque body filled with white pellets. Imprinted in black ink barr over 200 mg on one piece and 588 on the other piece.
250 mg: Two-piece hard gelatin capsule with blue opaque cap and white opaque body filled with white pellets. Imprinted in black ink barr over 250 mg on one piece and 589 on the other piece.
400 mg: Two-piece hard gelatin capsule with red opaque cap and white opaque body filled with white pellets. Imprinted in black ink barr over 400 mg on one piece and 590 on the other piece.
These recommendations are based on either drug interaction studies or observed clinical toxicities.
Coadministration of Didanosine and allopurinol is contraindicated because systemic exposures of Didanosine are increased, which may increase Didanosine-associated toxicity [see ClinicalPharmacology (12.3)].
Coadministration of Didanosine and ribavirin is contraindicated because exposures of the active metabolite of Didanosine (dideoxyadenosine 5’-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both Didanosine and ribavirin.
Fatal and nonfatal pancreatitis has occurred during therapy with Didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Didanosine delayed-release capsules should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with Didanosine delayed-release capsules in combination with stavudine may be at increased risk for pancreatitis.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of Didanosine delayed-release capsules therapy is recommended. In patients with risk factors for pancreatitis, Didanosine delayed-release capsules should be used with extreme caution and only if clearly indicated. Patients with advanced HIV-1 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 Adverse Reactions (6)].
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 cases 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 Use in Specific Populations (8.1)]. Particular caution should be exercised when administering Didanosine delayed-release capsules 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 Didanosine delayed-release capsules should be suspended in any patient who develops clinical signs or symptoms with or without laboratory findings consistent with symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
The safety and efficacy of Didanosine delayed-release capsules 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 [see Adverse Reactions (6)].
Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of Didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of Didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.
Patients receiving Didanosine delayed-release capsules should be monitored for early signs of portal hypertension (eg, thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. Didanosine delayed-release capsules should be discontinued in patients with evidence of non-cirrhotic portal hypertension.
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. Discontinuation of Didanosine delayed-release capsules should be considered in patients who develop peripheral neuropathy [see AdverseReactions (6)].
Retinal changes and optic neuritis have been reported in patients taking Didanosine. Periodic retinal examinations should be considered for patients receiving Didanosine delayed-release capsules [see Adverse Reactions (6)].
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Didanosine delayed-release capsules. 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 jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
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 long-term consequences of these events are currently unknown. A causal relationship has not been established.
The following adverse reactions are discussed in greater detail in other sections:
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.
Adults
Study AI454-152 was a 48-week, randomized, open-label study comparing Didanosine delayed-release capsules (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients. Selected clinical adverse reactions that occurred in combination with other antiretroviral agents are provided in Table 3.
| ||
| Percent of Patients†,‡ | ||
| Adverse Reactions | Didanosine delayed-release capsules + stavudine + nelfinavir n = 258 | zidovudine/ lamivudine§+ nelfinavir n = 253 |
| Diarrhea | 57 | 58 |
| Peripheral Neurologic Symptoms/Neuropathy | 25 | 11 |
| Nausea | 24 | 36 |
| Headache | 22 | 17 |
| Rash | 14 | 12 |
| Vomiting | 14 | 19 |
| Pancreatitis (see below) | less than 1 | ¶ |
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 delayed-release capsules plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received Didanosine plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz [see Warnings and Precautions (5)].
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 a study of Didanosine delayed-release capsules in combination with other antiretroviral agents are shown in Table 4.
| ||||
| Percent of Patients† | ||||
| Didanosine delayed-release capsules + stavudine + nelfinavir n = 258 | zidovudine/lamivudine‡ + nelfinavir n = 253 | |||
| Parameter | Grades 3 to 4§ | All Grades | Grades 3 to 4§ | All Grades |
| SGOT (AST) | 5 | 46 | 5 | 19 |
| SGPT (ALT) | 6 | 44 | 5 | 22 |
| Lipase | 5 | 23 | 2 | 13 |
| Bilirubin | less than 1 | 9 | less than 1 | 3 |
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/m2/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/m2 every 12 hours and in less than 1% of the 274 pediatric patients who received Didanosine 90 mg/m2 every 12 hours in combination with zidovudine [see Clinical Studies (14)].
Retinal changes and optic neuritis have been reported in pediatric patients.
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 (5.8) ].
Digestive Disorders - anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders - pancreatitis (including fatal cases) [see Warnings and Precautions
(5.1)], sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hepatobiliary Disorders - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.2)]; non-cirrhotic portal hypertension [see Warnings and Precautions (5.4)]; 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 (5.6)].
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 delayed-release capsules 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 [see Warnings and Precautions (5)]. The combination of Didanosine delayed-release capsules and hydroxyurea, with or without stavudine, should be avoided.
Clinical recommendations based on the results of drug interaction studies are listed in Table 5. Pharmacokinetic results of drug interaction studies are shown in Tables 9 to 12 [see Contraindications (4.1 and 4.2), Clinical Pharmacology (12.3)].
| ↑ Indicates increase. ↓ Indicates decrease. | ||
| ||
| Drug | Effect | Clinical Comment |
| ganciclovir | ↑Didanosine concentration | If there is no suitable alternative to ganciclovir, then use in combination with Didanosine delayed-release capsules with caution. Monitor for Didanosine-associated toxicity. |
| methadone | ↓Didanosine concentration | If coadministration of methadone and Didanosine is necessary, the recommended formulation of Didanosine is Didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when Didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with Didanosine pediatric powder due to significant decreases in Didanosine concentrations. |
| nelfinavir | No interaction 1 hour after Didanosine | Administer nelfinavir 1 hour after Didanosine delayed-release capsules. |
tenofovir disoproxil fumarate | ↑Didanosine concentration | A dose reduction of Didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended.*
Patients should be monitored for Didanosine-associated toxicities and clinical response. |
Exposure to Didanosine is increased when coadministered with tenofovir disoproxil fumarate
[Table 5 and see Clinical Pharmacokinetics (12.3, Tables 9 and 10)]. Increased exposure may cause or worsen Didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir disoproxil fumarate with Didanosine delayed-release capsules should be undertaken with caution, and patients should be monitored closely for Didanosine-related toxicities and clinical response. Didanosine delayed-release capsules should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop [see Dosage and Administration (2.3), Warnings and Precautions (5)]. Suppression of CD4 cell counts has been observed in patients receiving tenofovir disoproxil fumarate with Didanosine at a dose of 400 mg daily.
Predicted drug interactions with Didanosine delayed-release capsules are listed in Table 6.
| ↑ Indicates increase. | ||
| ||
| Drug or Drug Class | Effect | Clinical Comment |
| Drugs that may cause pancreatic toxicity | ↑risk of pancreatitis | Use only with extreme caution.* |
| Neurotoxic drugs | ↑risk of neuropathy | Use with caution.† |
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 (5.2)]. 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.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to Didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
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.
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 (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. Additional pharmacokinetic studies in pediatric patients support use of Didanosine delayed-release capsules in pediatric patients who weigh at least 20 kg.
In an Expanded Access Program using a buffered formulation of Didanosine for the treatment of advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) [see Warnings and Precautions (5.1)]. Clinical studies of Didanosine, including those for Didanosine delayed-release capsules, 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 [see Dosage and Administration (2.2)].
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 [see Clinical Pharmacology (12.3)]. A dose reduction is recommended for these patients [see Dosage and Administration (2)].
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, hyperuricemia, and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis [see Clinical Pharmacology (12.3)].
Didanosine delayed-release capsules are an enteric-coated formulation of Didanosine, USP, a synthetic purine nucleoside analogue active against HIV-1. Each Didanosine delayed-release capsule containing enteric-coated pellets, for oral administration, contains 200 mg, 250 mg or 400 mg of Didanosine, USP. In addition each capsule contains the following inactive ingredients: black iron oxide, croscarmellose sodium, D&C yellow no. 10 aluminum lake, FD&C blue no. 1, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, gelatin, hydroxypropyl cellulose, hypromellose, methacrylic acid copolymer dispersion, microcrystalline cellulose, polydextrose, polyethylene glycol, propylene glycol, shellac glaze, silicon dioxide, sodium hydroxide, talc, titanium dioxide, triacetin and triethyl citrate. The 200 mg and 400 mg capsule also contains D&C red no. 33 and FD&C yellow no. 6, and the 250 mg also contains D&C red no. 28.
The chemical name for Didanosine is 2' ,3' -dideoxyinosine. The structural formula is:
C10H12N4O3 M.W. 236.2
Didanosine is a white crystalline powder. The aqueous solubility of Didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH less than 3 and 37° C, 10% of Didanosine decomposes to hypoxanthine in less than 2 minutes. In Didanosine delayed-release capsules, an enteric coating is used to protect Didanosine from degradation by stomach acid.
Didanosine is an antiviral agent [see Clinical Pharmacology (12.4)].
The pharmacokinetic parameters of Didanosine in HIV-infected adult and pediatric patients are summarized in Table 7, 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 mean (± standard deviation) 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.
| ||||
| Pediatrics | Adults | |||
| Parameter* | 20 kg to less than 25 kg n = 10 | 25 kg to less than 60 kg n = 17 | At least 60 kg n = 7 | At least 60 kg n = 44 |
| Apparent clearance (L/h) | 89.5 + 21.6 | 116.2 + 38.6 | 196 + 55.8 | 174.5 + 69.7 |
| Apparent volume of distribution (L) | 98.1 + 30.2 | 154.7 + 55 | 363 + 137.7 | 308.3 + 164.3 |
| Elimination half-life (h) | 0.75 + 0.13 | 0.92 + 0.09 | 1.26 + 0.19 | 1.19 + 0.21 |
| Steady-state (AUC) (mg•h/L) | 2.38 + 0.66 | 2.36 + 0.70 | 2.25 + 0.89 | 2.65 + 1.07 |
Comparison of Didanosine Formulations
In Didanosine delayed-release capsules, the active ingredient, Didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the pellets in the capsule. The enteric coating dissolves when the pellets empty into the small intestine, the site of drug absorption. With buffered formulations of Didanosine, administration with antacid provides protection from degradation by stomach acid.
In healthy volunteers, as well as subjects infected with HIV-1, the AUC is equivalent for Didanosine administered as the Didanosine delayed-release capsules formulation relative to a buffered tablet formulation. The peak plasma concentration (Cmax) of Didanosine, administered as Didanosine delayed-release capsules, is reduced approximately 40% relative to Didanosine buffered tablets. The time to the peak concentration (Tmax) increases from approximately 0.67 hours for Didanosine buffered tablets to 2 hours for Didanosine delayed-release capsules.
