Videx EC Side Effects

Generic Name: didanosine

Please note - some side effects for Videx EC may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Videx EC - for the Consumer

Videx EC Delayed-Release Enteric-Coated Capsules

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Videx EC Delayed-Release Enteric-Coated Capsules:

Breast enlargement; changes in body fat; darkened complexion with purple markings; diarrhea; dry mouth; headache; itching; muscle pain; skin and facial wasting.

Seek medical attention right away if any of these SEVERE side effects occur when using Videx EC Delayed-Release Enteric-Coated Capsules:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blood in the vomit or vomit that looks like coffee grounds; blurred vision or other vision changes; chest pain or discomfort, numbness of an arm or leg, or shortness of breath; confusion; dark urine; dizziness; fainting; fast, shallow breathing; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; lightheadedness; low body temperature; nausea or vomiting; numbness, tingling, or pain in the hands or feet; pale stools; seizures; severe muscle pain or cramping; stomach pain or swelling; tiredness; unusual bruising or bleeding; weakness; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Videx EC Side Effects - for the Professional

Videx EC

The following adverse reactions are discussed in greater detail in other sections:

• Pancreatitis [see Boxed Warning, Warnings and Precautions (5.1)]
• Lactic acidosis/severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.2)]
• Hepatic toxicity [see Warnings and Precautions (5.3)]
• Non-cirrhotic portal hypertension [see Warnings and Precautions (5.4)]
• Peripheral neuropathy [see Warnings and Precautions (5.5)]
• Retinal changes and optic neuritis [see Warnings and Precautions (5.6)]

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.

Adults

Study Al454-152 was a 48-week, randomized, 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 (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.

Table 3: Selected Clinical Adverse Reactions, Study AI454-152a

Adverse Reactions	Percent of Patientsb,c
	VIDEX EC + stavudine + nelfinavir n=258	zidovudine/lamivudined + nelfinavir n=253
a Median duration of treatment was 62 weeks in the Videx EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c The incidences reported included all severity grades and all reactions regardless of causality.
d Zidovudine/lamivudine combination tablet.
* This event was not observed in this study arm.
Diarrhea	57	58
Peripheral Neurologic Symptoms/Neuropathy	25	11
Nausea	24	36
Headache	22	17
Rash	14	12
Vomiting	14	19
Pancreatitis	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 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 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 Videx EC in combination with other antiretroviral agents are shown in Table 4.

Table 4: Selected Laboratory Abnormalities, Study AI454-152a

	Percent of Patientsb
	Videx EC + stavudine + nelfinavir n=258		zidovudine/lamivudinec + nelfinavir n=253
Parameter	Grades 3-4d	All Grades	Grades 3-4d	All Grades
a Median duration of treatment was 62 weeks in the Videx EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group.
b Percentages based on treated patients.
c Zidovudine/lamivudine combination tablet.
d Greater than 5 x ULN for SGOT and SGPT, at least 2.1 x ULN for lipase, and at least 2.6 x ULN for bilirubin (ULN = upper limit of normal).
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.

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 (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 Videx EC 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 Videx EC and hydroxyurea, with or without stavudine, should be avoided.

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Side Effects by Body System - for Healthcare Professionals

General

The adverse effects of didanosine are sometimes difficult to distinguish from the symptomatology observed during the clinical course of AIDS, as well as from the possible adverse effects of other drugs used in the treatment of HIV infection. During the Expanded Access Program (EAP), adverse effects resulted in drug discontinuation in 42% of patients with AIDS and 34% of patients with ARC.

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. Patients treated with didanosine in combination with stavudine, with or without hydroxyurea, may be at an increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy.

Many of the side effects associated with nucleoside reverse transcriptase inhibitor therapy (myopathy, pancreatitis, liver failure, lactic acidosis, etc.) are attributable to their direct toxic effect on mitochondria which causes decreased mitochondrial energy-generating capacity.

Patients with renal dysfunction may be at increased risk of toxicity due to decreased clearance of didanosine.

Gastrointestinal

The frequency of pancreatitis is dose related. In phase 3 trials with buffered formulations, incidence ranged from 1% to 10% with doses higher than currently recommended and 1% to 7% with recommended doses.

The factors that increase the risk of pancreatitis in patients with HIV infection are an AIDS diagnosis, CD4+ cell count less than 100 cells/mm3, baseline hyperamylasemia, substantial alcohol intake, elevated liver transaminases, concurrent treatment with pancreatotoxic medications, and prior history. Resolution is generally seen 2 to 3 weeks following discontinuation of therapy, although fatal cases have been reported. Permanent discontinuation of didanosine in patients developing pancreatitis is suggested, because rechallenge often results in recurrent disease.

A retrospective cohort study evaluated the risk of pancreatitis with didanosine combination therapy. Patients with HIV can develop pancreatitis from the virus itself or from direct toxicity of several antiretroviral drugs.

Gastrointestinal side effects have included diarrhea (up to 70%), nausea (up to 53%), vomiting (30%), elevated lipase (Grades 3 to 4: up to 8%; all Grades: up to 26%), abdominal pain (up to 13%), and pancreatitis (up to 7%). Pancreatitis resulting in death has been reported during clinical trials of didanosine in combination with other antiretroviral agents. During the EAP in which patients received clinically recommended dosages, the incidence at 5 months for pancreatitis, increased amylase, or abdominal pain was 5% to 8%. Anorexia, dyspepsia, flatulence, pancreatitis (including fatal cases), dry mouth, sialoadenitis, and parotid gland enlargement have been reported during postmarketing experience.

Hepatic

Hepatic side effects have included lactic acidosis/severe hepatomegaly with steatosis, hepatic toxicity, and elevated AST (Grades 3 to 4: up to 9%; all Grades: up to 53%), ALT (Grades 3 to 4: up to 9%; all Grades: up to 50%), bilirubin (Grades 3 to 4: up to 16%; all Grades: up to 68%), and gamma-glutamyltransferase (greater than 5 times ULN: up to 5%; all Grades: up to 28%). Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. In addition, fulminant hepatitis has been associated with didanosine and has resulted in death. Symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis, noncirrhotic portal hypertension, hepatitis, and liver failure have been reported during postmarketing experience. Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing experience with hydroxyurea and other antiretroviral agents.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretroviral agents. 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. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents.

Hyperlactatemia and lactic acidosis are often a life-threatening and serious concern with the use of didanosine in combination with other antiretrovirals. Lactate elevation is a common issue in patients on stable antiretroviral therapy and increased levels without acidosis may result from increased production, release, or diminished clearance.

HIV reverse transcriptase inhibitors are competitive inhibitors of DNA polymerase and the greatest affinity appears to be in the mitochondria. Depletion of mitochondrial DNA diminishes cellular respiratory function leading to increased production of lactic acid. Excess lactic acid leaks out of the cell into systemic circulation and can progress to lactic acidosis if hydrogen ions drop the blood pH. Additionally, disturbances in metabolic homeostasis with antiretrovirals can cause hypertriglyceridemia and insulin resistance leading to steatohepatitis and decreased liver function.

Hyperlactatemia appears to be more common with didanosine while lactic acidosis is an infrequent occurrence.

In a report following patients on combined therapy with didanosine and tenofovir, one patient developed didanosine-related toxicity characterized by lactic acidosis with liver failure after 3 months on didanosine 200 mg/day with tenofovir.

Safety and efficacy 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 rate of liver function abnormalities, including severe and potentially fatal hepatic side effects.

Nervous system

Peripheral neuropathy occurred in 16% of patients treated during the EAP. Early trials of didanosine therapy reported a higher incidence. Those studies, however, used higher dosages than more recent trials using lower therapeutic dosages and early trials included patients with very advanced HIV disease. One-year rates of developing peripheral neuropathy ranged from 6% to 15% in the latter trials.

Neuropathy presents as tingling, numbness, or pain in the hands or soles of the feet which progresses up the legs. The incidence is higher in patients with a history of neuropathy and/or low CD4+ cell counts (less than 50 cells/mm3). Following discontinuation of didanosine, neuropathy usually resolves within 2 to 12 weeks.

Nervous system side effects have included headache (up to 46%), peripheral neurologic symptoms/neuropathy (up to 26%), insomnia, restlessness, and seizures.

Metabolic

There has been one case report of acute gouty arthritis developing 14 weeks after didanosine was added to the treatment regimen of a patient receiving ritonavir, both known to infrequently cause hyperuricemia. The symptoms resolved upon discontinuation of didanosine and a short course of indomethacin.

Metabolic side effects have included elevated alkaline phosphatase (greater than 5 times ULN: up to 4%), amylase (at least 1.4 times ULN: up to 17%; greater than 2 times ULN: up to 8%; all Grades: up to 31%), and uric acid (greater than 12 mg/dL: up to 3%). Hyperuricemia developed in 4% of patients treated during the EAP. At least one case of acute gouty arthritis has been reported. Diabetes mellitus, redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance"), hypoglycemia, hyperglycemia, and elevated serum uric acid, serum alkaline phosphatase, serum amylase, and serum gamma-glutamyltransferase have been reported during postmarketing experience.

Dermatologic

Dermatologic side effects have included rash (up to 30%), rash/pruritus (up to 9%), and at least one case of cutaneous leukocytoclastic vasculitis. Alopecia has been reported during postmarketing experience.

Hematologic

Hematologic side effects have included anemia, neutropenia, and thrombocytopenia. Leukopenia, anemia, and thrombocytopenia have also been reported during postmarketing experience. Thrombocytopenia and splenomegaly have been reported as early signs of noncirrhotic portal hypertension, which has been reported during postmarketing experience.

Cardiovascular

Cardiovascular side effects have rarely included dyspnea, orthopnea, edema, pericarditis, and left ventricular failure. Underlying cardiomyopathy may have been aggravated by treatment with buffered formulations, which had high sodium content.

Ocular

Diffuse dysfunction of the retinal epithelium has been reported in two patients during therapy with didanosine. Both patients experienced bilateral visual deficit including night blindness and a peripheral visual fold reduction. Symptoms were first noted after 31 and 34 weeks of therapy. Deficits in both patients appeared to be partially reversible upon discontinuation of didanosine.

Ocular side effects have included retinal changes and optic neuritis. Diffuse dysfunction of the retinal epithelium with bilateral visual deficit (including night blindness and a peripheral visual fold reduction) has been reported. Dry eyes, retinal depigmentation, and optic neuritis have been reported during postmarketing experience.

Other

Other side effects have included abdominal pain, asthenia, chills/fever, and pain during postmarketing experience.

Musculoskeletal

Musculoskeletal side effects have included myalgia (with or without increases in creatine kinase), rhabdomyolysis (including acute renal failure and hemodialysis), arthralgia, and myopathy during postmarketing experience.

Hypersensitivity

Hypersensitivity side effects have included anaphylactoid reaction during postmarketing experience.

Immunologic

Immunologic side effects have included immune reconstitution syndrome. Autoimmune disorders (e.g., Graves' disease, polymyositis, and Guillain-Barre syndrome) have been reported in the setting of immune reconstitution.

Endocrine

Endocrine side effects are uncommon but have included hypertriglyceridemia, impaired glucose tolerance, hyperglycemia, and hypoglycemia. Insulin-dependent diabetes mellitus has also been reported.

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