Megavir

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Megavir uses


WARNING: PANCREATITIS, LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS

Fatal and nonfatal pancreatitis has occurred during therapy with Megavir used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Megavir 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 Megavir and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of Megavir and stavudine with other antiretroviral agents. The combination of Megavir 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) ].

WARNING: PANCREATITIS, LACTIC ACIDOSIS and

HEPATOMEGALY with STEATOSIS

See full prescribing information for complete boxed warning.

  • Fatal and nonfatal pancreatitis. Megavir should be suspended in patients with suspected pancreatitis and discontinued in patients with confirmed pancreatitis. (5.1)
  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Fatal lactic acidosis has been reported in pregnant women who received the combination of Megavir and stavudine. (5.2)
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1 INDICATIONS AND USAGE

VIDEX® EC (didanosine, USP), 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) ].

Megavir (didanosine, USP) is a nucleoside reverse transcriptase inhibitor for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV)-1 infection. (1)

2 DOSAGE AND ADMINISTRATION

Megavir should be administered on an empty stomach. Megavir Delayed-Release Capsules should be swallowed intact.

  • Adult patients: Administered on an empty stomach. Dosing is based on body weight.
  • Pediatric patients: Ages 6 to 18 years, can safely swallow capsules and body weight at least 20 kg. Administered on an empty stomach, dosing is based on body weight. (2.1)

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

  • Renal impairment: Dose reduction is recommended. (2.2)
  • Coadministration with tenofovir: Dose reduction is recommended. Patients should be monitored closely for didanosine-associated adverse reactions. (2.3, 7.1)

2.1 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 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. Please consult the complete prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for dosage and administration of Megavir 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

2.2 Renal Impairment

Dosing recommendations for Megavir and VIDEX Pediatric Powder for Oral Solution are different for patients with renal impairment. Please consult the complete prescribing information on administration of VIDEX Pediatric Powder for Oral Solution to patients with renal impairment.

Adult Patients

In adult patients with impaired renal function, the dose of Megavir should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of Megavir 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
a Based on studies using a buffered formulation of Megavir.

b Not suitable for use in patients less than 60 kg with CLcr less than 10 mL/min. An alternate formulation of Megavir should be used.


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

Pediatric Patients

Urinary excretion is also a major route of elimination of Megavir in pediatric patients, therefore the clearance of Megavir may be altered in pediatric patients with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of Megavir in this patient population, a reduction in the dose should be considered.

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 Megavir following hemodialysis.

2.3 Dose Adjustment

Concomitant Therapy with Tenofovir Disoproxil Fumarate

In patients who are also taking tenofovir disoproxil fumarate, a dose reduction of Megavir to 250 mg 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 Megavir 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 and Precautions (5.3) and Clinical Pharmacology (12.3) ].

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3 DOSAGE FORMS AND STRENGTHS

Megavir (didanosine, USP) Delayed-Release Capsules are white, opaque capsules as described below:

  • 125 mg capsule imprinted with “BMS 125 mg 6671” in Tan
  • 200 mg capsule imprinted with “BMS 200 mg 6672” in Green
  • 250 mg capsule imprinted with “BMS 250 mg 6673” in Blue
  • 400 mg capsule imprinted with “BMS 400 mg 6674” in Red

Capsules: 125 mg, 200 mg, 250 mg, 400 mg (3)

4 CONTRAINDICATIONS

These recommendations are based on either drug interaction studies or observed clinical toxicities.

Coadministration with allopurinol or ribavirin is contraindicated.

4.1 Allopurinol

Coadministration of Megavir and allopurinol is contraindicated because systemic exposures of Megavir are increased, which may increase didanosine-associated toxicity [see Clinical Pharmacology (12.3) ].

4.2 Ribavirin

Coadministration of Megavir and ribavirin is contraindicated because exposures of the active metabolite of Megavir (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 Megavir and ribavirin.

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5 WARNINGS AND PRECAUTIONS

  • Pancreatitis: Suspension or discontinuation of Megavir may be necessary.
  • Lactic acidosis and severe hepatomegaly with steatosis: Suspend Megavir in patients who develop clinical symptoms or signs with or without laboratory findings. (5.2)
  • Hepatic toxicity: Interruption or discontinuation of Megavir must be considered upon worsening of liver disease. (5.3)
  • Non-cirrhotic portal hypertension: Discontinue Megavir in patients with evidence of non-cirrhotic portal hypertension. (5.4)
  • Patients may develop peripheral neuropathy (5.5), retinal changes and optic neuritis (5.6), immune reconstitution syndrome (5.7), and redistribution/accumulation of body fat (5.8).

5.1 Pancreatitis

Fatal and nonfatal pancreatitis has occurred during therapy with Megavir used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Megavir should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with Megavir 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 Megavir (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, Megavir 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) .]

5.2 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 Megavir 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 Megavir and stavudine with other antiretroviral agents. The combination of Megavir 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 ]. Particular caution should be exercised when administering Megavir 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 Megavir 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).

5.3 Hepatic Toxicity

The safety and efficacy of Megavir 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, Megavir, and stavudine. This combination should be avoided. [See Adverse Reactions (6) .]

5.4 Non-cirrhotic Portal Hypertension

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 Megavir therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.

Patients receiving Megavir should be monitored for early signs of portal hypertension 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. Megavir should be discontinued in patients with evidence of non-cirrhotic portal hypertension.

5.5 Peripheral Neuropathy

Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving Megavir 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 Megavir should be considered in patients who develop peripheral neuropathy. [See Adverse Reactions (6) .]

5.6 Retinal Changes and Optic Neuritis

Retinal changes and optic neuritis have been reported in patients taking Megavir. Periodic retinal examinations should be considered for patients receiving Megavir [see Adverse Reactions ].

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Megavir. 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.

5.8 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 long-term consequences of these events are currently unknown. A causal relationship has not been established.

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6 ADVERSE REACTIONS

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 (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) ]
  • In adults, the most common adverse reactions (greater than 10%, all grades) are diarrhea, peripheral neurologic symptoms/neuropathy, nausea, headache, rash, and vomiting. (6.1)
  • Adverse reactions in pediatric patients were consistent with those in adults. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 AI454-152 was a 48-week, randomized, open-label study comparing Megavir 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.

Adverse Reactions Percent of Patientsb,c
Megavir + stavudine

+ nelfinavir

n=258

zidovudine/lamivudined

+ nelfinavir

n=253

a Median duration of treatment was 62 weeks in the Megavir + 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 Megavir, pancreatitis resulting in death was observed in one patient who received Megavir plus stavudine plus nelfinavir, one patient who received Megavir plus stavudine plus indinavir, and 2 of 68 patients who received Megavir plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received Megavir 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 Megavir, 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 Megavir in combination with other antiretroviral agents are shown in Table 4.

Percent of Patientsb
Megavir + 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 Megavir + 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 × ULN for SGOT and SGPT, at least 2.1 × ULN for lipase, and at least 2.6 × 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 Megavir. Adverse reactions and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of Megavir 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 Megavir 120 mg/m2 every 12 hours and in less than 1% of the 274 pediatric patients who received Megavir 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Megavir. 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 Megavir, 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 (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 Megavir is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when Megavir is used alone. Thus, patients treated with Megavir 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 Megavir and hydroxyurea, with or without stavudine, should be avoided.

7 DRUG INTERACTIONS

Coadministration of Megavir can alter the concentration of other drugs and other drugs may alter the concentration of Megavir. The potential drug-drug interactions must be considered prior to and during therapy.

7.1 Established Drug Interactions

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 9-12 [see Contraindications (4.1 and 4.2), Clinical Pharmacology (12.3) ].

Drug Effect Clinical Comment
↑ Indicates increase.

↓ Indicates decrease.

a Coadministration of Megavir with food decreases Megavir concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce Megavir concentrations further.


ganciclovir


↑ Megavir concentration


If there is no suitable alternative to ganciclovir, then use in combination with Megavir with caution. Monitor for didanosine-associated toxicity.


methadone


↓ Megavir concentration


If coadministration of methadone and Megavir is necessary, the recommended formulation of Megavir is Megavir. Patients should be closely monitored for adequate clinical response when Megavir is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in Megavir concentrations.


nelfinavir


No interaction 1 hour after Megavir


Administer nelfinavir 1 hour after Megavir.


tenofovir disoproxil fumarate


↑ Megavir concentration


A dose reduction of Megavir 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.a

  • 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min)
  • 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min)

Patients should be monitored for didanosine-associated toxicities and clinical response.


Exposure to Megavir 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 Megavir should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. Megavir 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 Megavir at a dose of 400 mg daily.

7.2 Predicted Drug Interactions

Predicted drug interactions with Megavir are listed in Table 6.

Drug or Drug Class Effect Clinical Comment
↑ Indicates increase.

a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of Megavir is recommended [see Warnings and Precautions (5.1) ].

b [See Warnings and Precautions (5.6) .]


Drugs that may cause pancreatic toxicity


↑ risk of pancreatitis


Use only with extreme caution.a


Neurotoxic drugs


↑ risk of neuropathy


Use with caution.b

8 USE IN SPECIFIC POPULATIONS

Pregnancy: Fatal lactic acidosis has been reported in pregnant women who received both Megavir and stavudine with other agents. This combination should be used with caution during pregnancy and only if the potential benefit clearly outweighs the potential risk. Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263.

8.1 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, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to Megavir. At approximately 12 times the estimated human exposure, Megavir 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 Megavir 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 Megavir in pregnant women. Megavir 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 Megavir 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 Megavir 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 Megavir 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 Megavir and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, Megavir and/or its metabolites were excreted into the milk of lactating rats. It is not known if Megavir 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 breastfeed if they are receiving Megavir.

8.4 Pediatric Use

Use of Megavir in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of Megavir in adult and pediatric patients [see Dosage and Administration, Adverse Reactions (6.1), Clinical Pharmacology (12.3) , and Clinical Studies (14) ]. Additional pharmacokinetic studies in pediatric patients support use of Megavir in pediatric patients who weigh at least 20 kg.

8.5 Geriatric Use

In an Expanded Access Program using a buffered formulation of Megavir 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 Megavir, including those for Megavir, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Megavir 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) ].

8.6 Renal Impairment

Patients with renal impairment (creatinine clearance of less than 60 mL/min) may be at greater risk of toxicity from Megavir due to decreased drug clearance [see Clinical Pharmacology (12.3) ]. A dose reduction is recommended for these patients [see Dosage and Administration (2) ].

10 OVERDOSAGE

There is no known antidote for Megavir overdosage. In phase 1 studies, in which buffered formulations of Megavir were initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction. Megavir is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis [see Clinical Pharmacology (12.3) ].

11 DESCRIPTION

VIDEX® EC is the brand name for an enteric-coated formulation of Megavir, USP, a synthetic purine nucleoside analogue active against HIV-1. Megavir Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of Megavir. The inactive ingredients in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain gelatin and titanium dioxide. The capsules are imprinted with edible inks.

Megavir is also available in a powder formulation. Please consult the prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for additional information.

The chemical name for Megavir is 2′,3′-dideoxyinosine. The structural formula is:

Megavir is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of Megavir at 25° C and pH of approximately 6 is 27.3 mg/mL. Megavir is unstable in acidic solutions. For example, at pH less than 3 and 37° C, 10% of Megavir decomposes to hypoxanthine in less than 2 minutes. In Megavir, an enteric coating is used to protect Megavir from degradation by stomach acid.

didanosine-structure.jpg

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Megavir is an antiviral agent [see Clinical Pharmacology ].

12.3 Pharmacokinetics

The pharmacokinetic parameters of Megavir in HIV-infected adult and pediatric patients are summarized in Table 7, by weight ranges that correspond to recommended doses (Table 1). Megavir 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 Megavir 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 Megavir 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 Megavir 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 Megavir in man occurs by the same pathways responsible for the elimination of endogenous purines.

a The pharmacokinetic parameters (mean ± standard deviation) of Megavir were determined by a population pharmacokinetic model based on combined clinical studies.

Parametera


Pediatrics


Adults


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


196.0 ± 55.8


174.5 ± 69.7


Apparent volume of distribution (L)


98.1 ± 30.2


154.7 ± 55.0


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 Megavir Formulations

In Megavir, the active ingredient, Megavir, is protected against degradation by stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric coating dissolves when the beadlets empty into the small intestine, the site of drug absorption. With buffered formulations of Megavir, 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 Megavir administered as the Megavir formulation relative to a buffered tablet formulation. The peak plasma concentration of Megavir, administered as Megavir, is reduced approximately 40% relative to Megavir buffered tablets. The time to the peak concentration (Tmax) increases from approximately 0.67 hours for Megavir buffered tablets to 2.0 hours for Megavir.

Effect of Food

In the presence of food, the Cmax and AUC for Megavir were reduced by approximately 46% and 19%, respectively, compared to the fasting state [see Dosage and Administration (2) ]. Megavir should be taken on an empty stomach.

Special Populations

Renal Insufficiency: Data from two studies using a buffered formulation of Megavir indicated that the apparent oral clearance of Megavir decreased and the terminal elimination half-life increased as creatinine clearance decreased. Following oral administration, Megavir 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 Megavir was not affected in patients requiring dialysis. [See Dosage and Administration (2.2) .]

Parameter Creatinine Clearance (mL/min) Dialysis Patients

n=11

at least 90

n=12

60-90

n=6

30-59

n=6

10-29

n=3

ND = not determined due to anuria.

CLcr = creatinine clearance.

CL/F = apparent oral clearance.

CLR = renal clearance.


CLcr (mL/min)


112 ± 22


68 ± 8


46 ± 8


13 ± 5


ND


CL/F (mL/min)


2164 ± 638


1566 ± 833


1023 ± 378


628 ± 104


543 ± 174


CLR (mL/min)


458 ± 164


247 ± 153


100 ± 44


20 ± 8


less than 10


T½ (h)


1.42 ± 0.33


1.59 ± 0.13


1.75 ± 0.43


2.0 ± 0.3


4.1 ± 1.2


Hepatic Impairment: The pharmacokinetics of Megavir 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 Cmax values following a single 400 mg dose of Megavir 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 Cmax values was observed for subjects with hepatic impairment and matched healthy controls. [See Dosage and Administration (2.3) .]

Pediatric Patients: The pharmacokinetics of Megavir have been evaluated in HIV-exposed and HIV-infected pediatric patients from birth to adulthood.

A population pharmacokinetic analysis was conducted on pooled Megavir 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. Megavir exposure similar to that at recommended adult doses can be achieved in pediatric patients with a weight-based dosing scheme [see Dosage and Administration (2) ].

Geriatric Patients: Megavir pharmacokinetics have not been studied in patients over 65 years of age [see Use in Specific Populations (8.5) ].

Gender: The effects of gender on Megavir pharmacokinetics have not been studied.

Drug Interactions

Tables 9 and 10 summarize the effects on AUC and Cmax, with a 90% confidence interval (CI) when available, following coadministration of Megavir with a variety of drugs. For clinical recommendations based on drug interaction studies for drugs in bold font, see Dosage and Administration (2.3) and Drug Interactions (7.1) .

% Change of Megavir

Pharmacokinetic Parametersa

Drug Megavir Dosage n AUC of

Megavir

(90% CI)

Cmax of

Megavir

(90% CI)

↑ Indicates increase.

↓ Indicates decrease.

↔ Indicates no change, or mean increase or decrease of less than 10%.

a The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.

b All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.

c Tenofovir disoproxil fumarate.

d 373 kcalories, 8.2 grams fat.

e Compared with Megavir 250 mg administered alone under fasting conditions.

f Compared with Megavir 400 mg administered alone under fasting conditions.

g Comparisons are made to historical controls (n=148, pooled from 5 studies) conducted in healthy subjects. The number of subjects evaluated for AUC and Cmax is 15 and 16, respectively.


tenofovir,b,c 300 mg

once daily with a light meald


400 mg single dose fasting

2 hours before tenofovir


26


↑ 48%

(31, 67%)


↑ 48%

(25, 76%)


tenofovir,b,c 300 mg

once daily with a light meald


400 mg single dose

with tenofovir and a light meal


25


↑ 60%

(44, 79%)


↑ 64%

(41, 89%)


tenofovir,b,c 300 mg

once daily with a light meald


200 mg single dose

with tenofovir and a light meal


33


↑ 16%

(6, 27%)e


↓ 12%

(-25, 3%)e




250 mg single dose

with tenofovir and a light meal


33



(-13, 5%)f


↓ 20%

(-32, -7%)f




325 mg single dose

with tenofovir and a light meal


33


↑ 13%

(3, 24%)f


↓ 11%

(-24, 4%)f


methadone, chronic maintenance dose


400 mg single dose


15, 16g


↓ 17%

(-29, -2%)


↓ 16%

(-33, 4%)

% Change of Coadministered Drug

Pharmacokinetic Parametersa,b

Drug Megavir Dosage n AUC of Coadministered Drug

(90% CI)

Cmax of Coadministered Drug

(90% CI)

↔ Indicates no change, or mean increase or decrease of less than 10%.

a The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.

b All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.

c Tenofovir disoproxil fumarate.

d 373 kcalories, 8.2 grams fat.


ciprofloxacin, 750 mg

single dose


400 mg single dose


16






indinavir, 800 mg

single dose


400 mg single dose


23






ketoconazole, 200 mg

single dose


400 mg single dose


21






tenofovir,c 300 mg

once daily with a light meald


400 mg single dose

fasting 2 hours before tenofovir


25






tenofovir,c 300 mg

once daily with a light meald


400 mg single dose

with tenofovir and a light meal


25






Megavir Buffered Formulations: Tables 11 and 12 summarize the effects on AUC and Cmax, with a 90% or 95% CI when available, following coadministration of buffered formulations of Megavir with a variety of drugs. The results of these studies may be expected to apply to Megavir. For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. For clinical recommendations based on drug interaction studies for drugs in bold font, see Dosage and Administration (2.3 for Concomitant Therapy with Tenofovir Disoproxil Fumarate), Contraindications (4.1), and Drug Interactions (7.1) .

% Change of Megavir

Pharmacokinetic Parametersa

Drug Megavir Dosage n AUC of Megavir

(95% CI)

Cmax of Megavir

(95% CI)

↑ Indicates increase.

↓ Indicates decrease.

↔ Indicates no change, or mean increase or decrease of less than 10%.

a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.

b 90% CI.

c HIV-infected patients.

NA = Not available.


allopurinol,

renally impaired, 300 mg/day


200 mg single dose


2


↑ 312%


↑ 232%


healthy volunteer, 300 mg/day

for 7 days


400 mg single dose


14


↑ 113%


↑ 69%


ganciclovir, 1000 mg every 8 hours,

2 hours after Megavir


200 mg every 12 hours


12


↑ 111%


NA


ciprofloxacin, 750 mg every 12 hours for 3 days, 2 hours before Megavir


200 mg every 12 hours

for 3 days


8c


↓ 16%


↓ 28%


indinavir, 800 mg single dose










simultaneous


200 mg single dose


16






1 hour before Megavir


200 mg single dose


16


↓ 17%

(-27, -7%)b


↓ 13%

(-28, 5%)b


ketoconazole, 200 mg/day for 4 days,

2 hours before Megavir


375 mg every 12 hours

for 4 days


12c




↓ 12%


loperamide, 4 mg every 6 hours for 1 day


300 mg single dose


12c




↓ 23%


metoclopramide, 10 mg single dose


300 mg single dose


12c




↑ 13%


ranitidine, 150 mg single dose,

2 hours before Megavir


375 mg single dose


12c


↑ 14%


↑ 13%


rifabutin, 300 mg or 600 mg/day for 12 days


167 mg or 250 mg every 12 hours

for 12 days


11


↑ 13%

(-1, 27%)


↑ 17%

(-4, 38%)


ritonavir, 600 mg every 12 hours for 4 days


200 mg every 12 hours

for 4 days


12


↓ 13%

(0, 23%)


↓ 16%

(5, 26%)


stavudine, 40 mg every 12 hours for 4 days


100 mg every 12 hours

for 4 days


10






sulfamethoxazole, 1000 mg single dose


200 mg single dose


8c






trimethoprim, 200 mg single dose


200 mg single dose


8c




↑ 17%

(-23, 77%)


zidovudine, 200 mg every 8 hours for 3 days


200 mg every 12 hours

for 3 days


6c





% Change of Coadministered Drug

Pharmacokinetic Parametersa

Drug Megavir Dosage n AUC of Coadministered Drug

(95% CI)

Cmax of Coadministered Drug

(95% CI)

↑ Indicates increase.

↓ Indicates decrease.

↔ Indicates no change, or mean increase or decrease of less than 10%.

a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.

b HIV-infected patients.

NA = Not available.


dapsone, 100 mg single dose


200 mg every 12 hours for 14 days


6b






ganciclovir, 1000 mg every 8 hours,

2 hours after Megavir


200 mg every 12 hours


12b


↓ 21%


NA


nelfinavir, 750 mg single dose,

1 hour after Megavir


200 mg single dose


10b


↑ 12%




ranitidine, 150 mg single dose,

2 hours before Megavir


375 mg single dose


12b


↓ 16%




ritonavir, 600 mg every 12 hours for 4 days


200 mg every 12 hours

for 4 days


12






stavudine, 40 mg every 12 hours for 4 days


100 mg every 12 hours

for 4 days


10b




↑ 17%


sulfamethoxazole, 1000 mg single dose


200 mg single dose


8b


↓ 11%

(-17, -4%)


↓ 12%

(-28, 8%)


trimethoprim, 200 mg single dose


200 mg single dose


8b


↑ 10%

(-9, 34%)


↓ 22%

(-59, 49%)


zidovudine, 200 mg every 8 hours for 3 days


200 mg every 12 hours

for 3 days


6b


↓ 10%

(-27, 11%)


↓ 16.5%

(-53, 47%)

12.4 Microbiology

Mechanism of Action

Megavir is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3′-hydroxyl group is replaced by hydrogen. Intracellularly, Megavir 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.

Antiviral Activity in Cell Culture

The anti-HIV-1 activity of Megavir was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% ranged from 2.5 to 10 μM (1 μM = 0.24 μg/mL) in lymphoblastic cell lines and 0.01 to 0.1 μM in monocyte/macrophage cell cultures.

Resistance

HIV-1 isolates with reduced sensitivity to Megavir have been selected in cell culture and were also obtained from patients treated with Megavir. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V substitution was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of Megavir monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to Megavir in cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in Megavir susceptibility harbored one or more Megavir resistance-associated substitutions.

Cross-resistance

HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with Megavir and zidovudine exhibited decreased susceptibility to Megavir, lamivudine, stavudine, zalcitabine, and zidovudine in cell culture. These isolates harbored five substitutions (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to Megavir.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure.

Megavir induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses.

Megavir was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.

13.2 Animal Toxicology and/or Pharmacology

Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with Megavir at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of Megavir to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of Megavir and other nucleoside analogues.

14 CLINICAL STUDIES

14.1 Adult Patients

Study AI454-152 was a 48-week, randomized, open-label study comparing Megavir 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, 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-1 RNA less than 400 and less than 50 copies/mL and outcomes of patients through 48 weeks are summarized in Figure 1 and Table 13, respectively.

Outcome Percent of Patients with HIV-1 RNA less than 400 copies/mL

(less than 50 copies/mL)

Megavir + stavudine

+ nelfinavir

n=258

zidovudine/lamivudinea

+ nelfinavir

n=253

a Zidovudine/lamivudine combination tablet.

b Corresponds to rates at Week 48 in Figure 1.

c Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.

d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.

e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated, and other reasons.


Responderb,c


55% (33%)


56% (33%)


Virologic failured


22% (45%)


21% (43%)


Death or discontinued due to disease progression


1% (1%)


2% (2%)


Discontinued due to adverse event


6% (6%)


7% (7%)


Discontinued due to other reasonse


16% (16%)


15% (16%)

Megavir figure

14.2 Pediatric Patients

Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 every 6 hours), Megavir (120 mg/m2 every 12 hours), or zidovudine (120 mg/m2 every 6 hours) plus Megavir (90 mg/m2 every 12 hours). Patients treated with Megavir or Megavir plus zidovudine had lower rates of HIV-1 disease progression or death compared with those treated with zidovudine alone.

16 HOW SUPPLIED/STORAGE AND HANDLING

Megavir (didanosine, USP) Delayed-Release Capsules are white, opaque capsules that are packaged in bottles with child-resistant closures as described in Table 14.


125 mg capsule imprinted with “BMS 125 mg 6671” in Tan


NDC No. 0087-6671-17


30 capsules/bottle


200 mg capsule imprinted with “BMS 200 mg 6672” in Green


NDC No. 0087-6672-17


30 capsules/bottle


250 mg capsule imprinted with “BMS 250 mg 6673” in Blue


NDC No. 0087-6673-17


30 capsules/bottle


400 mg capsule imprinted with “BMS 400 mg 6674” in Red


NDC No. 0087-6674-17


30 capsules/bottle


Storage

The capsules should be stored in tightly closed containers at 25° C (77° F). Excursions between 15° C and 30° C (59° F and 86° F) are permitted.

17 PATIENT COUNSELING INFORMATION

See Medication Guide.

17.1 Pancreatitis

Patients should be informed that a serious toxicity of Megavir, used alone and in combination regimens, is pancreatitis, which may be fatal.

17.2 Peripheral Neuropathy

Patients should be informed that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with Megavir. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV-1 disease or a history of peripheral neuropathy, and that discontinuation of Megavir may be required if toxicity develops.

17.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis

Patients should be informed that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Megavir and other antiretrovirals.

17.4 Hepatic Toxicity

Patients should be informed that hepatotoxicity including fatal hepatic adverse events were reported in patients with preexisting liver dysfunction. The safety and efficacy of Megavir have not been established in HIV-infected patients with significant underlying liver disease.

17.5 Non-cirrhotic Portal Hypertension

Patients should be informed that non-cirrhotic portal hypertension has been reported in patients taking Megavir, including cases leading to liver transplantation or death.

17.6 Retinal Changes and Optic Neuritis

Patients should be informed that retinal changes and optic neuritis have been reported in adult and pediatric patients.

17.7 Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

17.8 Concomitant Therapy

Patients should be informed that when Megavir is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when Megavir is used alone. These patients should be followed closely.

Patients should be cautioned about the use of medications or other substances, including alcohol, which may exacerbate Megavir toxicities.

17.9 General Information

Megavir is not a cure for HIV-1 infection, and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Therefore, patients should remain under the care of a physician when using Megavir.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
  • Do not breastfeed. It is not known if Megavir can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.

Patients should be instructed to swallow the capsule as a whole and to not open the capsule.

Patients should be instructed to not miss a dose but if they do, patients should take Megavir as soon as possible. Patients should be told that if it is almost time for the next dose, they should skip the missed dose and continue with the regular dosing schedule.

Patients should be instructed to contact a poison control center or emergency room right away in case of an overdose.

Medication Guide

VIDEX ® EC (VY-dex Ee-see)

(didanosine, also known as ddI)

Delayed-Release Capsules

Enteric-Coated Beadlets

Read this Medication Guide before you start taking Megavir and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. You and your healthcare provider should talk about your treatment with Megavir before you start taking it and at regular check-ups. You should stay under your healthcare provider’s care when taking Megavir.

What is the most important information I should know about Megavir?

Megavir may cause serious side effects, including:

1. Swelling of your pancreas (pancreatitis) that may cause death. Pancreatitis can happen at any time during your treatment with Megavir. Before you start taking Megavir, tell your healthcare provider if you:

  • have had pancreatitis
  • have advanced HIV (human immunodeficiency virus) infection
  • have kidney problems
  • drink alcoholic beverages
  • take a medicine called ZERIT® (stavudine)

It is important to call your healthcare provider right away if you have:

  • stomach pain
  • swelling of your stomach
  • nausea and vomiting
  • fever

2. Build-up of acid in your blood (lactic acidosis). Lactic acidosis must be treated in the hospital as it may cause death. Before you start taking Megavir, tell your healthcare provider if you:

  • have liver problems
  • are pregnant. There have been deaths reported in pregnant women who get lactic acidosis after taking Megavir and ZERIT (stavudine).
  • are overweight
  • have been treated for a long time with other medicines to treat HIV

It is important to call your healthcare provider right away if you:

  • feel weak or tired
  • have unusual (not normal) muscle pain
  • have trouble breathing
  • have stomach pain with nausea and vomiting
  • feel cold, especially in your arms and legs
  • feel dizzy or light-headed
  • have a fast or irregular heartbeat

3. Liver problems. Serious liver problems have happened in some people (including pregnant women) who take Megavir. These problems include liver enlargement (hepatomegaly), fat in the liver (steatosis), liver failure, and high blood pressure in the large vein of the liver (portal hypertension). Severe liver problems can lead to liver transplantation or death in some people taking Megavir. Your healthcare provider should check your liver function while you are taking Megavir. You should be especially careful if you have a history of heavy alcohol use or liver problems.

It is important to call your healthcare provider right away if you have:

  • yellowing of your skin or the white of your eyes (jaundice)
  • dark urine
  • pain on the right side of your stomach
  • swelling of your stomach
  • easy bruising or bleeding
  • loss of appetite
  • nausea or vomiting
  • vomiting blood or dark colored stools (bowel movements)

What is Megavir?

Megavir is a prescription medicine used with other antiretroviral medicines to treat human immunodeficiency virus (HIV) infection in children and adults. Megavir belongs to a class of drugs called nucleoside analogues.

Megavir will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking Megavir, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your healthcare provider regularly and report any medical problems that occur.

Who should not take Megavir?

Do not take Megavir if you take:

  • ZYLOPRIM®, LOPURIN®, ALOPRIM® (allopurinol)
  • COPEGUS®, REBETOL®, RIBASPHERE®, RIBAVIRIN®, VIRAZOLE® (ribavirin)

What should I tell my healthcare provider before taking Megavir?

Before you take Megavir, tell your healthcare provider if you:

  • have or had kidney problems
  • have or had liver problems (such as hepatitis)
  • have or had persistent numbness, tingling, or pain in the hands or feet (neuropathy)
  • have any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if Megavir will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking Megavir. You and your healthcare provider will decide if you should take Megavir while you are pregnant.

    Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.

  • are breastfeeding or plan to breastfeed. Do not breastfeed. It is not known if Megavir can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Megavir may affect the way other medicines work, and other medicines may affect how Megavir works.

Especially tell your healthcare provider if you take:

  • CYTOVENE®, VALCYTE® (ganciclovir)
  • DOLOPHINE® HYDROCHLORIDE, METHADOSE® (methadone)
  • VIRACEPT® (nelfinavir)
  • VIREAD® (tenofovir disoproxil fumarate)
  • alcoholic beverages

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

Ask your healthcare provider if you are not sure if you take one of the medicines listed above.

How should I take Megavir?

  • Take Megavir exactly as your healthcare provider tells you to take it.
  • Your healthcare provider will tell you how much Megavir to take and when to take it.
  • Your healthcare provider may change your dose. Do not change your dose of Megavir without talking to your healthcare provider.
  • Do not take Megavir with food. Take Megavir on an empty stomach.
  • Take Megavir capsules whole. Do not break, crush, dissolve, or chew Megavir capsules before swallowing. If you cannot swallow Megavir capsules whole, tell your healthcare provider. You may need a different medicine.
  • Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule.
  • Some medicines should not be taken at the same time of day that you take Megavir. Check with your healthcare provider.
  • If your kidneys are not working well, your healthcare provider will need to do regular blood and urine tests to check how they are working while you take Megavir. Your healthcare provider may also lower your dosage of Megavir if your kidneys are not working well.
  • If you take too much Megavir, contact a poison control center or emergency room right away.

What should I avoid while taking Megavir?

  • Alcohol. Do not drink alcohol while taking Megavir. Alcohol may increase your risk of getting pain and swelling of your pancreas (pancreatitis) or may damage your liver.

What are the possible side effects of Megavir?

Megavir can cause pancreatitis, lactic acidosis, and liver problems. See “What is the most important information I should know about Megavir?” at the beginning of this Medication Guide.

  • Vision changes. You should have regular eye exams while taking Megavir.
  • Peripheral neuropathy. Symptoms include: numbness, tingling, or pain in your hands or feet. This condition is more likely to happen in people who have had it before, in patients taking medicines that affect the nerves, and in people with advanced HIV disease. A child may not notice these symptoms. Ask the child’s healthcare provider for the signs and symptoms of peripheral neuropathy in children.
  • Changes in your immune system (immune reconstitution syndrome). Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new or worse symptoms of infection after you start taking HIV medicine.
  • Changes in body fat (fat redistribution). Changes in body fat have been seen in people who take antiretroviral medicines. These changes may include:
    • more fat in or around your
      • upper back and neck (buffalo hump)
      • breasts or chest
      • trunk
    • less fat in your
      • legs
      • arms
      • face

Tell your healthcare provider if you have any of the symptoms listed above.

The most common side effects of Megavir include:

  • diarrhea
  • stomach pain
  • nausea
  • vomiting
  • headache
  • rash

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Megavir. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Megavir?

  • Store Megavir capsules in a tightly closed container between 59° F to 86° F (15° C to 30° C)
  • Safely throw away any unused Megavir

Keep Megavir and all medicines out of the reach of children and pets.

General Information about the safe and effective use of Megavir

Avoid doing things that can spread HIV-1 infection to others.

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Megavir for a condition for which it was not prescribed. Do not give Megavir to other people, even if they have the same symptoms as you have. It may harm them.

Do not keep medicine that is out of date or that you no longer need. Dispose of unused medicines through community take-back disposal programs when available or place Megavir in an unrecognizable closed container in the household trash.

This Medication Guide summarizes the most important information about Megavir. If you would like more information about Megavir, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Megavir that is written for health professionals. For more information, go to www.bms.com/products/Pages/prescribing.aspx or call 1-800-321-1335.

What are the ingredients in Megavir?

Active Ingredients: Megavir

Inactive Ingredients:

Carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, talc, gelatin, and titanium dioxide.

VIDEX® EC and Zerit® are registered trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.

Distributed by:

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

Product of Japan

This Medication Guide has been approved by the U.S. Food and Drug Administration.

1352585

Revised August 2015

Megavir 125 mg Representative Packaging

See HOW SUPPLIED section for a complete list of available packages of Megavir.

30 Capsules NDC 0087-6671-17

125 mg

VIDEX®EC

(didanosine, USP)

delayed-release capsules

enteric-coated beadlets

Detach and dispense

the accompanying

Medication Guide

to the patient.

Rx only

Megavir 200 mg Representative Packaging

30 Capsules NDC 0087-6672-17

200 mg

VIDEX®EC

(didanosine, USP)

delayed-release capsules

enteric-coated beadlets

Detach and dispense

the accompanying

Medication Guide

to the patient.

Rx only

Megavir 250 mg Representative Packaging

30 Capsules NDC 0087-6673-17

250 mg

VIDEX®EC

(didanosine, USP)

delayed-release capsules

enteric-coated beadlets

Detach and dispense

the accompanying

Medication Guide

to the patient.

Rx only

Megavir 400 mg Representative Packaging

30 Capsules NDC 0087-6674-17

400 mg

VIDEX®EC

(didanosine, USP)

delayed-release capsules

enteric-coated beadlets

Detach and dispense

the accompanying

Medication Guide

to the patient.

Rx only

Megavir pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Megavir available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Megavir destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Megavir Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Megavir pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."VIDEX EC (DIDANOSINE) CAPSULE, DELAYED RELEASE [BRISTOL-MYERS SQUIBB COMPANY]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."DIDANOSINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "didanosine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Megavir?

Depending on the reaction of the Megavir after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Megavir not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Megavir addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Megavir, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Megavir consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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