DRUGS & SUPPLEMENTS

Stavex

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Stavex uses

Stavex consists of Lamivudine, Stavudine.

Lamivudine:


Stavex Mcneil & Argus Pharmaceuticals information

Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals is an anti-HIV treatment in the class of drugs called Nucleoside Reverse Transcriptase Inhibitors (NRTIs). The body breaks down these drugs into chemicals that stop HIV from infecting uninfected cells in the body, but they do not help cells that have already been infected with the virus. This product is an important part of combination anti-HIV treatment. Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals inhibits the reproduction of viruses in the body.

Stavex Mcneil & Argus Pharmaceuticals warnings

Before taking the medication, tell your doctor if you have:

kidney disease

liver disease

pancreatitis

problems with your muscles

problems with your blood counts.

Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals does not reduce the risk of passing the HIV or hepatitis B virus to others. Avoid alcohol while taking the medicine. Alcohol may increase the risk of damage to the pancreas and / or liver. It is not known whether Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals will be harmful to an unborn baby. It is very important to treat HIV / AIDS during pregnancy to reduce the risk of infecting the baby. It is not known whether Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals passes into breast milk and what effect it may have on a nursing baby. To prevent transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed. The drug may interact with other medications resulting in reduced effectiveness and / or side effects. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medications, including herbal products.

Stavex Mcneil & Argus Pharmaceuticals side effects

The possible side effects of Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals are lactic acidosis and severe liver problems, including fatal cases, have been reported with the use of reverse transcriptase inhibitors, alone or in combination. Contact your doctor immediately if you experience nausea, vomiting, or unusual or unexpected stomach discomfort; weakness and tiredness; shortness of breath; weakness in the arms and legs; yellowing of the skin or eyes; or pain in the upper stomach area. These may be early symptoms of lactic acidosis or liver problems. Serious cases of pancreatitis (inflammation of the pancreas) have also been reported with the use of Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals. Notify your doctor immediately if you develop symptoms of pancreatitis including nausea, vomiting, diarrhea, abdominal pain. If you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives), stop taking this medication and seek emergency medical attention.

Stavex Mcneil & Argus Pharmaceuticals overdose

Seek emergency medical attention. Symptoms of a Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals overdose are not known. Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication unless your doctor directs otherwise.

Stavex Mcneil & Argus Pharmaceuticals usage guidelines

Take this medicine exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you. Take each dose with a full glass of water. Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals can be taken with or without food. For the treatment of HIV or AIDS, this drug is usually taken twice a day and is often used in combination with other HIV medicines. Follow your doctor's instructions. For the treatment of chronic hepatitis B, this product is usually taken once a day. Follow your doctor's instructions. Store Stavex (Lamivudine) Mcneil & Argus Pharmaceuticals at room temperature away from moisture and heat.

Stavudine:


WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS; PANCREATITIS

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Stavex (Stavudine) and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of Stavex (Stavudine) and didanosine with other antiretroviral agents. The combination of Stavex (Stavudine) and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Warnings and Precautions (5.1) ].

Fatal and nonfatal pancreatitis have occurred during therapy when Stavex (Stavudine) was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression [see Warnings and Precautions (5.4) ].

WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with

STEATOSIS; PANCREATITIS

See full prescribing information for complete boxed warning.

  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Fatal lactic acidosis has been reported in pregnant women who received the combination of Stavex (Stavudine) and didanosine. (5.1)
  • Fatal and nonfatal pancreatitis have occurred when Stavex (Stavudine) was part of a combination regimen that included didanosine. (5.4)
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1    INDICATIONS AND USAGE

Stavex (Stavudine)® (stavudine), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14) ].

Stavex (Stavudine) (stavudine) 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

The interval between doses of Stavex (stavudine) should be 12 hours. Stavex (Stavudine) may be taken with or without food.

  • Recommended dosage for adults:
    • less than 60 kg: 30 mg every 12 hours (2.1)
    • at least 60 kg: 40 mg every 12 hours (2.1)
  • Recommended dosage for pediatric patients:
    • newborns from birth to 13 days old: 0.5 mg/kg every 12 hours (2.2)
    • at least 14 days old and weighing less than 30 kg: 1 mg/kg every 12 hours (2.2)
    • weighing at least 30 kg: adult dose (2.2)
  • Renal impairment: Dose adjustment is recommended for CrCl ≤50 mL/min. (2.3)
  • Oral solution: Requires preparation by a pharmacist. (2.4)

2.1    Recommended Adult Dosage

The recommended adult dosage is based on body weight as follows:

  • For patients weighing less than 60 kg: 30 mg every 12 hours.
  • For patients weighing at least 60 kg: 40 mg every 12 hours.

2.2    Recommended Pediatric Dosage

  • For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.
  • For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours.
  • For pediatric patients weighing at least 30 kg: use the recommended adult dosage.

2.3    Dosage Adjustment

Renal Impairment

Adult Patients: Stavex may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in Table 1.

Creatinine

Clearance

(mL/min)

Recommended Stavex (Stavudine) Dose

by Patient Weight

at least 60 kg less than 60 kg
* Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days.

greater than 50


40 mg every 12 hours


30 mg every 12 hours


26–50


20 mg every 12 hours


15 mg every 12 hours


10–25


20 mg every 24 hours


15 mg every 24 hours


Hemodialysis


20 mg every 24 hours*


15 mg every 24 hours*


Pediatric Patients: Since urinary excretion is also a major route of elimination of Stavex (Stavudine) in pediatric patients, the clearance of Stavex (Stavudine) may be altered in children with renal impairment. There are insufficient data to recommend a specific dose adjustment of Stavex (Stavudine) in this patient population.

2.4    Method of Preparation for Oral Solution

Prior to dispensing, the pharmacist must constitute the dry powder with purified water to a concentration of 1 mg Stavex (Stavudine) per mL of solution, as follows:

  • Add 202 mL of purified water to the container.
  • Shake container vigorously until the powder dissolves completely. Constitution in this way produces 200 mL (deliverable volume) of 1 mg/mL Stavex (Stavudine) solution. The solution may appear slightly hazy.
  • Dispense solution in original container with measuring cup provided. Instruct patient to shake the container vigorously prior to measuring each dose and to store the tightly closed container in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.
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3    DOSAGE FORMS AND STRENGTHS

  • Stavex (Stavudine) 15 mg capsules with dark red cap and light yellow body, printed with black ink “BMS 1964” on the cap and with black ink “15” on the body.
  • Stavex (Stavudine) 20 mg capsules with light brown cap and light brown body, printed with black ink “BMS 1965” on the cap and with black ink “20” on the body.
  • Stavex (Stavudine) 30 mg capsules with dark orange cap and light orange body, printed with black ink “BMS 1966” on the cap and with black ink “30” on the body.
  • Stavex (Stavudine) 40 mg capsules with dark orange cap and dark orange body, printed with black ink “BMS 1967” on the cap and with black ink “40” on the body.
  • Stavex (Stavudine) for oral solution is a dye-free, fruit-flavored powder that provides 1 mg of Stavex (Stavudine) per milliliter solution after constitution.
  • Capsules: 15 mg, 20 mg, 30 mg, 40 mg (3, 16.1)
  • Oral solution: 1 mg/mL following constitution (3, 16.2)

4    CONTRAINDICATIONS

Stavex (Stavudine) is contraindicated in patients with clinically significant hypersensitivity to Stavex (Stavudine) or to any of the components contained in the formulation.

Stavex (Stavudine) is contraindicated in patients with clinically significant hypersensitivity to Stavex (Stavudine) or to any of the components of this product. (4)

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5    WARNINGS AND PRECAUTIONS

  • Lactic acidosis/severe hepatomegaly with steatosis: Suspend treatment with Stavex in patients who develop clinical symptoms or signs with or without laboratory findings. (5.1)
  • Hepatic toxicity: May be severe, fatal. Consider interruption or discontinuation. Avoid use in combination with didanosine and hydroxyurea. Risk of hepatic decompensation exists when used in combination with interferon and ribavirin; closely monitor and consider discontinuation of Stavex (Stavudine). (5.2)
  • Neurologic symptoms: Motor weakness, most often seen in the setting of lactic acidosis, may mimic Guillain-Barré syndrome; discontinue treatment. Monitor for peripheral neuropathy, which can be severe; treatment discontinuation should be considered. (5.3)
  • Pancreatitis: Suspend treatment, resume with particular caution and close monitoring and avoid use in combination with didanosine. (5.4)
  • Patients may develop redistribution/accumulation of body fat, monitor for signs and symptoms of lipoatrophy/lipodystrophy. Alternative antiretrovirals should be considered. (5.5)
  • Patients may develop immune reconstitution syndrome. (5.6)

5.1    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 Stavex (Stavudine) and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing Stavex (Stavudine). Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of Stavex (Stavudine) and didanosine with other antiretroviral agents. The combination of Stavex (Stavudine) and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Use in Specific Populations (8.1) ].

Particular caution should be exercised when administering Stavex (Stavudine) to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness [see Warnings and Precautions (5.3) ] might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.

Treatment with Stavex (Stavudine) (stavudine) should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Permanent discontinuation of Stavex (Stavudine) should be considered for patients with confirmed lactic acidosis.

5.2    Hepatic Toxicity

The safety and efficacy of Stavex have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and Stavex (Stavudine). This combination should be avoided. [See Adverse Reactions (6) .]

Use with Interferon and Ribavirin-Based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as Stavex (Stavudine). Although no evidence of a pharmacokinetic or pharmacodynamic (eg, loss of HIV-1/HCV virologic suppression) interaction was seen when ribavirin was coadministered with Stavex (Stavudine) in HIV-1/HCV co-infected patients [see Drug Interactions (7) ], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon and ribavirin. Patients receiving interferon with or without ribavirin and Stavex (Stavudine) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of Stavex (Stavudine) should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (eg, Child-Pugh >6) (see the full prescribing information for interferon and ribavirin).

5.3    Neurologic Symptoms

Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including Stavex. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops, Stavex (Stavudine) should be discontinued. Symptoms may continue or worsen following discontinuation of therapy.

Peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving Stavex (Stavudine) therapy. Peripheral neuropathy, which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine [see Adverse Reactions (6) ].

Patients should be monitored for the development of peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of Stavex (Stavudine) should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy.

5.4    Pancreatitis

Fatal and nonfatal pancreatitis have occurred during therapy when Stavex (Stavudine) was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of Stavex (Stavudine) and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of Stavex (Stavudine) after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine.

5.5    Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with Stavex (Stavudine) compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from Stavex (Stavudine) to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving Stavex (Stavudine) should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using Stavex (Stavudine) including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.

5.6    Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Stavex (Stavudine). 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.

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6    ADVERSE REACTIONS

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

  • lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning and Warnings and Precautions ]
  • hepatic toxicity [see Warnings and Precautions (5.2) ]
  • neurologic symptoms and motor weakness [see Warnings and Precautions (5.3) ]
  • pancreatitis [see Boxed Warning and Warnings and Precautions (5.4) ]
  • lipoatrophy/lipodystrophy [see Warnings and Precautions (5.5) ]

When Stavex (Stavudine) is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when Stavex (Stavudine) is used alone.

  • In adults, the most common adverse reactions are headache, diarrhea, neuropathy, rash, nausea, and vomiting. (6.1)
  • Adverse reactions in pediatric patients were consistent with those seen in adults. (6.2)

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 Trial Experience in Adults

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 clinical practice.

Selected adverse reactions that occurred in adult patients receiving Stavex (Stavudine) in a controlled monotherapy study (Study AI455-019) are provided in Table 2.

Percent (%)
Adverse Reaction Stavex (Stavudine)b

(40 mg twice daily)

(n=412)

zidovudine

(200 mg 3 times daily)

(n=402)

a  The incidences reported included all severity grades and all reactions regardless of causality.

b  Median duration of Stavex (Stavudine) therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.


Headache


54


49


Diarrhea


50


44


Peripheral Neurologic

     Symptoms/Neuropathy


52


39


Rash


40


35


Nausea and Vomiting


39


44


Pancreatitis was observed in 3 of the 412 adult patients who received Stavex (Stavudine) in study AI455-019.

Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving Stavex (Stavudine) from two controlled combination studies are provided in Table 3.

Percent (%)
START 1 START 2b
Adverse Reaction Stavex (Stavudine) +

lamivudine +

indinavir

(n=100c)

zidovudine +

lamivudine +

indinavir

(n=102)

Stavex (Stavudine) +

didanosine +

indinavir

(n=102c)

zidovudine +

lamivudine +

indinavir

(n=103)

a  The incidences reported included all severity grades and all reactions regardless of causality.

b  START 2 compared two triple-combination regimens in 205 treatment-naive patients. Patients received either Stavex (Stavudine) (40 mg twice daily) plus didanosine plus indinavir or zidovudine plus lamivudine plus indinavir.

c  Duration of Stavex (Stavudine) therapy = 48 weeks.


Nausea


43


63


53


67


Diarrhea


34


16


45


39


Headache


25


26


46


37


Rash


18


13


30


18


Vomiting


18


33


30


35


Peripheral Neurologic

     Symptoms/Neuropathy


8


7


21


10


Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4.

Percent (%)
Parameter Stavex (Stavudine)

(40 mg twice daily)

(n=412)

zidovudine

(200 mg 3 times daily)

(n=402)

a  Data presented for patients for whom laboratory evaluations were performed.

b  Median duration of Stavex (Stavudine) therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.

ULN = upper limit of normal.


AST (SGOT)

     (>5.0 × ULN)


11


10


ALT (SGPT)

     (>5.0 × ULN)


13


11


Amylase

     (≥1.4 × ULN)


14


13


Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6.

Percent (%)
START 1 START 2
Parameter Stavex (Stavudine) +

lamivudine +

indinavir

(n=100)

zidovudine +

lamivudine +

indinavir

(n=102)

Stavex (Stavudine) +

didanosine +

indinavir

(n=102)

zidovudine +

lamivudine +

indinavir

(n=103)

ULN = upper limit of normal.

Bilirubin

     (>2.6 × ULN)


7


6


16


8


AST (SGOT)

     (>5 × ULN)


5


2


7


7


ALT (SGPT)

     (>5 × ULN)


6


2


8


5


GGT

     (>5 × ULN)


2


2


5


2


Lipase

     (>2 × ULN)


6


3


5


5


Amylase

     (>2 × ULN)


4


<1


8


2

Percent (%)
START 1 START 2
Parameter Stavex (Stavudine) +

lamivudine +

indinavir

(n=100)

zidovudine +

lamivudine +

indinavir

(n=102)

Stavex (Stavudine) +

didanosine +

indinavir

(n=102)

zidovudine +

lamivudine +

indinavir

(n=103)


Total Bilirubin


65


60


68


55


AST (SGOT)


42


20


53


20


ALT (SGPT)


40


20


50


18


GGT


15


8


28


12


Lipase


27


12


26


19


Amylase


21


19


31


17

6.2    Clinical Trial Experience in Pediatric Patients

Adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients. [See Use in Specific Populations .]

6.3    Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of Stavex (Stavudine). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to Stavex (Stavudine), or a combination of these factors.

  • Body as a Whole: abdominal pain, allergic reaction, chills/fever, and redistribution/accumulation of body fat [see Warnings and Precautions (5.5) ].
  • Digestive Disorders: anorexia.
  • Exocrine Gland Disorders: pancreatitis, including fatal cases [see Warnings and Precautions (5.4) ].
  • Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis.
  • Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.1) ], hepatitis and liver failure.
  • Metabolic Disorders: lipoatrophy, lipodystrophy [see Warnings and Precautions (5.5) ], diabetes mellitus and hyperglycemia.
  • Musculoskeletal: myalgia.
  • Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) [see Warnings and Precautions (5.1 , 5.3) ].

Use with Didanosine- and Hydroxyurea-Based Regimens

When Stavex (Stavudine) is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when Stavex (Stavudine) is used alone. Thus, patients treated with Stavex (Stavudine) in combination with didanosine, 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 Stavex (Stavudine) and hydroxyurea, with or without didanosine, should be avoided.

7    DRUG INTERACTIONS

Stavex (Stavudine) is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.

Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of Stavex (Stavudine). Therefore, use of zidovudine in combination with Stavex (Stavudine) (stavudine) should be avoided.

Doxorubicin: In vitro data indicate that the phosphorylation of Stavex (Stavudine) is inhibited at relevant concentrations by doxorubicin. The clinical significance of this interaction is unknown; therefore, concomitant use of Stavex (Stavudine) with doxorubicin should be undertaken with caution.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, Stavex (Stavudine), and zidovudine. The clinical significance of the interaction with Stavex (Stavudine) is unknown; therefore, concomitant use of Stavex (Stavudine) with ribavirin should be undertaken with caution. No pharmacokinetic (eg, plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (eg, loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), Stavex (Stavudine) (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.2) ].

  • Coadministration of Stavex (Stavudine) with zidovudine should be avoided. (7)
  • Coadministration of Stavex (Stavudine) and doxorubicin or ribavirin should be undertaken with caution. (7)

8    USE IN SPECIFIC POPULATIONS

  • Pregnancy: Fatal lactic acidosis has been reported in pregnant women who received both didanosine and Stavex with other agents. This combination should be used with caution during pregnancy and only if the potential benefit clearly outweighs the potential risk to the fetus. Pregnancy registry available. (8.1)
  • Nursing mothers should be instructed not to breastfeed due to the potential for postnatal HIV transmission. (8.3)

8.1    Pregnancy

Pregnancy Category C

Reproduction studies have been performed in rats and rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that Stavex (Stavudine) is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. Animal reproduction studies are not always predictive of human response.

There are no adequate and well-controlled studies of Stavex (Stavudine) in pregnant women. Stavex (Stavudine) 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 Stavex (Stavudine) and didanosine 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 Boxed Warning and Warnings and Precautions (5.1) ]. The combination of Stavex (Stavudine) and didanosine 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 Stavex (Stavudine) 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 Stavex (Stavudine) 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. Studies in lactating rats demonstrated that Stavex is excreted in milk. Although it is not known whether Stavex (Stavudine) is excreted in human milk, there exists the potential for adverse effects from Stavex (Stavudine) in nursing infants. 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 Stavex (Stavudine).

8.4    Pediatric Use

Use of Stavex (Stavudine) in pediatric patients from birth through adolescence is supported by evidence from adequate and well-controlled studies of Stavex (Stavudine) in adults with additional pharmacokinetic and safety data in pediatric patients [see Dosage and Administration (2.2) and Adverse Reactions (6.2) ].

Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of Stavex (Stavudine) in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received Stavex (Stavudine) 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received Stavex (Stavudine) 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received Stavex (Stavudine) 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.

Stavex (Stavudine) pharmacokinetics have been evaluated in 25 HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV or oral administration of single doses and twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens [see Clinical Pharmacology (12.3, Table 9) ].

8.5    Geriatric Use

Clinical studies of Stavex (stavudine) did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of Stavex (Stavudine) cannot be ruled out.

In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy.

Stavex (Stavudine) 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, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3) ].

8.6    Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of Stavex (Stavudine) decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the Stavex (Stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

10    OVERDOSAGE

Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavex (Stavudine) can be removed by hemodialysis; the mean ± SD hemodialysis clearance of Stavex (Stavudine) is 120 ± 18 mL/min. Whether Stavex (Stavudine) is eliminated by peritoneal dialysis has not been studied.

11    DESCRIPTION

Stavex (Stavudine)® is the brand name for Stavex (Stavudine) (d4T), a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus type 1 (HIV-1). The chemical name for Stavex (Stavudine) is 2′,3′-didehydro-3′-deoxythymidine. Stavex (Stavudine) has the following structural formula:

Stavex (Stavudine) is a white to off-white crystalline solid with the molecular formula C10H12N2O4 and a molecular weight of 224.2. The solubility of Stavex (Stavudine) at 23°C is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of Stavex (Stavudine) at 23°C is 0.144.

Capsules: Stavex (Stavudine) is available as capsules for oral administration containing either 15, 20, 30, or 40 mg of Stavex (Stavudine). Each capsule also contains inactive ingredients microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate. The hard gelatin shell consists of gelatin, titanium dioxide, and iron oxides. The capsules are printed with edible inks.

Powder for Oral Solution: Stavex (Stavudine) is available as a dye-free, fruit-flavored powder in bottles with child-resistant closures providing 200 mL of a 1 mg/mL Stavex (Stavudine) oral solution upon constitution with water per label instructions. The powder for oral solution contains the following inactive ingredients: methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming and flavoring agents.

Stavex (Stavudine) chemical structure

12    CLINICAL PHARMACOLOGY

12.1    Mechanism of Action

Stavex is an antiviral drug [see Clinical Pharmacology (12.4) ].

12.3    Pharmacokinetics

The pharmacokinetics of Stavex (Stavudine) have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of Stavex (Stavudine) with repeated administration every 6, 8, or 12 hours.

Absorption

Following oral administration, Stavex is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to Stavex (Stavudine) is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of Stavex (Stavudine) (stavudine) in HIV-1-infected adults are shown in Table 7.

Parameter Stavex (Stavudine) 40 mg BID

Mean ± SD (n=8)

AUC0–24 = Area under the curve over 24 hours.

Cmax = Maximum plasma concentration.

Cmin = Trough or minimum plasma concentration.


AUC0–24 (ng-h/mL)


2568 ± 454


Cmax (ng/mL)


536 ± 146


Cmin (ng/mL)


8 ± 9

Distribution

Binding of Stavex (Stavudine) to serum proteins was negligible over the concentration range of 0.01 to 11.4 µg/mL. Stavex (Stavudine) distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 8.

Metabolism

Metabolism plays a limited role in the clearance of Stavex. Unchanged Stavex (Stavudine) was the major drug-related component circulating in plasma after an 80-mg dose of 14C-stavudine, while metabolites constituted minor components of the circulating radioactivity. Minor metabolites include oxidized Stavex (Stavudine), glucuronide conjugates of Stavex (Stavudine) and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of Stavex (Stavudine).

Elimination

Following an 80-mg dose of 14C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. Radioactivity due to parent drug in urine and feces was 73.7% and 62.0%, respectively. The mean terminal elimination half-life is approximately 2.3 hours following single oral doses. Mean renal clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of the apparent oral clearance.

In HIV-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 8). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Parameter Mean ± SD n
a  Following 1-hour IV infusion.

b  Following single oral dose.

c  Assuming a body weight of 70 kg.

d  Over 12–24 hours.


Oral bioavailability (%)


86.4 ± 18.2


25


Volume of distribution (L)a


46 ± 21


44


Total body clearance (mL/min)a


594 ± 164


44


Apparent oral clearance (mL/min)b


560 ± 182c


113


Renal clearance (mL/min)a


237 ± 98


39


Elimination half-life, IV dose (h)a


1.15 ± 0.35


44


Elimination half-life, oral dose (h)b


1.6 ± 0.23


8


Urinary recovery of Stavex (Stavudine) (% of dose)a,d


42 ± 14


39

Special Populations

Pediatric

Pharmacokinetic parameters of Stavex in pediatric patients are presented in Table 9.

Parameter Ages 5 weeks

to 15 years

n Ages 14

to 28 days

n Day

of Birth

n
a  Following 1-hour IV infusion.

b  At median time of 2.5 hours (range 2–3 hours) following multiple oral doses.

c  Following single oral dose.

d  Over 8 hours.

ND = Not determined.


Oral

     bioavailability (%)


76.9 ± 31.7


20


ND


ND


Volume of

     distribution (L/kg)a


0.73 ± 0.32


21


ND


ND


Ratio of CSF: plasma

     concentrations (as %)b


59 ± 35


8


ND


ND


Total body clearance

     (mL/min/kg)a


9.75 ± 3.76


21


ND


ND


Apparent oral clearance

     (mL/min/kg)c


13.75 ± 4.29


20


11.52 ± 5.93


30


5.08 ± 2.80


17


Elimination half-life,

     IV dose (h)a


1.11 ± 0.28


21


ND


ND


Elimination half-life,

     oral dose (h)c


0.96 ± 0.26


20


1.59 ± 0.29


30


5.27 ± 2.01


17


Urinary recovery of

     stavudine (% of dose)c,d


34 ± 16


19


ND


ND

Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of Stavex (Stavudine) decreased and the terminal elimination half-life increased as creatinine clearance decreased. Cmax and Tmax were not significantly altered by renal impairment. The mean ± SD hemodialysis clearance value of Stavex (Stavudine) was 120 ± 18 mL/min (n=12); the mean ± SD percentage of the Stavex (Stavudine) dose recovered in the dialysate, timed to occur between 2–6 hours post-dose, was 31 ± 5%. Based on these observations, it is recommended that Stavex (Stavudine) (stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3) ].

Creatinine Clearance Hemodialysis

Patientsb

(n=11)

>50 mL/min

(n=10)

26–50 mL/min

(n=5)

9–25 mL/min

(n=5)

a  Single 40-mg oral dose.

b  Determined while patients were off dialysis.

T½ = Terminal elimination half-life.

NA = Not applicable.


Creatinine clearance

     (mL/min)


104 ± 28


41 ± 5


17 ± 3


NA


Apparent oral

     clearance (mL/min)


335 ± 57


191 ± 39


116 ± 25


105 ± 17


Renal clearance

     (mL/min)


167 ± 65


73 ± 18


17 ± 3


NA


T½ (h)


1.7 ± 0.4


3.5 ± 2.5


4.6 ± 0.9


5.4 ± 1.4

Hepatic Impairment

Stavex pharmacokinetics were not altered in five non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40-mg dose.

Geriatric

Stavex (Stavudine) pharmacokinetics have not been studied in patients >65 years of age. [See Use in Specific Populations (8.5) .]

Gender

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between males and females (n=27).

Race

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between races (n=233 Caucasian, 39 African-American, 41 Hispanic, 1 Asian, and 4 other).

Drug Interaction Studies

Stavex does not inhibit the major cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Because Stavex (Stavudine) is not protein-bound, it is not expected to affect the pharmacokinetics of protein-bound drugs.

Tables 11 and 12 summarize the effects on AUC and Cmax, with a 95% confidence interval (CI) when available, following coadministration of Stavex (Stavudine) with didanosine, lamivudine, and nelfinavir. No clinically significant pharmacokinetic interactions were observed.

Drug Stavex (Stavudine)

Dosage

na AUC of

Stavex (Stavudine)

(95% CI)

Cmax of

Stavex (Stavudine)

(95% CI)

↑  Indicates increase.

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

a  HIV-1-infected patients.


Didanosine, 100 mg

     q12h for 4 days


40 mg q12h

for 4 days


10




↑ 17%


Lamivudine, 150 mg

     single dose


40 mg single

dose


18



(92.7–100.6%)


↑ 12%

(100.3–126.1%)


Nelfinavir, 750 mg

     q8h for 56 days


30–40 mg q12h

for 56 days


8





Drug Stavex (Stavudine)

Dosage

na AUC of

Coadministered

Drug

(95% CI)

Cmax of

Coadministered

Drug

(95% CI)

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

a  HIV-1-infected patients.


Didanosine, 100 mg

     q12h for 4 days


40 mg q12h for

4 days


10






Lamivudine, 150 mg

     single dose


40 mg single

dose


18



(90.5–107.6%)



(87.1–110.6%)


Nelfinavir, 750 mg

     q8h for 56 days


30–40 mg q12h

for 56 days


8





12.4    Microbiology

Mechanism of Action

Stavex, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite Stavex (Stavudine) triphosphate. Stavex (Stavudine) triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (Ki=0.0083 to 0.032 µM) and by causing DNA chain termination following its incorporation into viral DNA. Stavex (Stavudine) triphosphate inhibits cellular DNA polymerases β and γ and markedly reduces the synthesis of mitochondrial DNA.

Antiviral Activity in Cell Culture

The cell culture antiviral activity of Stavex (Stavudine) was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. The concentration of drug necessary to inhibit HIV-1 replication by 50% (EC50) ranged from 0.009 to 4 µM against laboratory and clinical isolates of HIV-1. In cell culture, Stavex (Stavudine) exhibited additive to antagonistic activity in combination with zidovudine. Stavex (Stavudine) in combination with either abacavir, didanosine, tenofovir, or zalcitabine exhibited additive to synergistic anti-HIV-1 activity. Ribavirin, at the 9–45 µM concentrations tested, reduced the anti-HIV-1 activity of Stavex (Stavudine) by 2.5- to 5-fold. The relationship between cell culture susceptibility of HIV-1 to Stavex (Stavudine) and the inhibition of HIV-1 replication in humans has not been established.

Resistance

HIV-1 isolates with reduced susceptibility to Stavex have been selected in cell culture (strain-specific) and were also obtained from patients treated with Stavex (Stavudine). Phenotypic analysis of HIV-1 isolates from 61 patients receiving prolonged (6–29 months) Stavex (Stavudine) monotherapy showed that post-therapy isolates from four patients exhibited EC50 values more than 4-fold (range 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. Of these, HIV-1 isolates from one patient contained the zidovudine-resistance-associated substitutions T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated substitution Q151M. Mutations in the RT gene of HIV-1 isolates from the other two patients were not detected. The genetic basis for Stavex (Stavudine) susceptibility changes has not been identified.

Cross-resistance

Cross-resistance among HIV-1 reverse transcriptase inhibitors has been observed. Several studies have demonstrated that prolonged Stavex (Stavudine) treatment can select and/or maintain thymidine analogue mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) associated with zidovudine resistance. HIV-1 isolates with one or more TAMs exhibited reduced susceptibility to Stavex (Stavudine) in cell culture. These TAMs are seen at a similar frequency with Stavex (Stavudine) and zidovudine in virological treatment. The clinical relevance of these findings suggests that Stavex (Stavudine) should be avoided in the presence of thymidine analogue mutations.

13    NONCLINICAL TOXICOLOGY

13.1    Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies in mice and rats, Stavex (Stavudine) was noncarcinogenic at doses which produced exposures (AUC) 39 and 168 times, respectively, human exposure at the recommended clinical dose. Benign and malignant liver tumors in mice and rats and malignant urinary bladder tumors in male rats occurred at levels of exposure 250 (mice) and 732 (rats) times human exposure at the recommended clinical dose.

Stavex (Stavudine) was not mutagenic in the Ames, E. coli reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation. Stavex (Stavudine) produced positive results in the in vitro human lymphocyte clastogenesis and mouse fibroblast assays, and in the in vivo mouse micronucleus test. In the in vitro assays, Stavex (Stavudine) elevated the frequency of chromosome aberrations in human lymphocytes (concentrations of 25 to 250 µg/mL, without metabolic activation) and increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25 to 2500 µg/mL, with and without metabolic activation). In the in vivo micronucleus assay, Stavex (Stavudine) was clastogenic in bone marrow cells following oral Stavex (Stavudine) administration to mice at dosages of 600 to 2000 mg/kg/day for 3 days.

No evidence of impaired fertility was seen in rats with exposures (based on Cmax) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.

14    CLINICAL STUDIES

Combination Therapy

The combination use of Stavex is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents.

One of these studies (START 1) was a multicenter, randomized, open-label study comparing Stavex (Stavudine) (40 mg twice daily) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude of inhibition of HIV-1 RNA levels and increases in CD4+ cell counts through 48 weeks.

Monotherapy

The efficacy of Stavex (Stavudine) was demonstrated in a randomized, double-blind study (AI455-019, conducted 1992–1994) comparing Stavex (Stavudine) with zidovudine in 822 patients with a spectrum of HIV-1-related symptoms. The outcome in terms of progression of HIV-1 disease and death was similar for both drugs.

16    HOW SUPPLIED/STORAGE AND HANDLING

16.1    Capsules

Stavex ® (stavudine) Capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures:

Product

Strength

Capsule

Shell Color

Markings on Capsule

(in Black Ink)

Capsules

per Bottle

NDC No.

15 mg


Light yellow

& dark red


BMS

1964


15


60


0003-1964-01


20 mg


Light brown


BMS

1965


20


60


0003-1965-01


30 mg


Light orange

& dark orange


BMS

1966


30


60


0003-1966-01


40 mg


Dark orange


BMS

1967


40


60


0003-1967-01

16.2    Oral Solution

Stavex (Stavudine)® (stavudine) for Oral Solution is a dye-free, fruit-flavored powder that provides 1 mg of Stavex (Stavudine) per mL of solution upon constitution with water. Directions for solution preparation are included on the product label and in the Dosage and Administration (2) section of this insert. Stavex (Stavudine) for Oral Solution (NDC No. 0003-1968-01) is available in child-resistant containers that provide 200 mL of solution after constitution with water.

16.3    Storage

Stavex (Stavudine) 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.

Stavex (Stavudine) for Oral Solution should be protected from excessive moisture and stored in tightly closed containers at 25°C (77°F). Excursions between 15°C and 30°C (59°F and 86°F) are permitted. After constitution, store tightly closed containers of Stavex (Stavudine) for Oral Solution in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.

17    PATIENT COUNSELING INFORMATION

17.1    General

Patients should be advised that Stavex is not a cure for HIV-1 infection, and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using Stavex (Stavudine) and the importance of adherence to any antiretroviral regimen including those that contain Stavex (Stavudine).

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 Stavex (Stavudine) 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 informed that when Stavex (Stavudine) is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when Stavex (Stavudine) is used alone.

Patients should be instructed that if they miss a dose, to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue the regular dosing schedule.

Patients should be instructed if they take too much Stavex (Stavudine), they should contact a poison control center or emergency room right away.

Patients should be informed that the Centers for Disease Control and Prevention (CDC) recommend that HIV-infected mothers not nurse newborn infants to reduce the risk of postnatal transmission of HIV infection.

Patients with diabetes should be aware that Stavex (Stavudine) for Oral Solution contains 50 mg of sucrose (sugar) per mL.

17.2    Lactic Acidosis

Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or lactic acidosis syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of Stavex (Stavudine) therapy may be required.

17.3    Hepatic Toxicity

Patients should be informed that an increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with Stavex in combination with didanosine and hydroxyurea. This combination should be avoided.

17.4    Peripheral Neuropathy

Patients should be informed that an important toxicity of Stavex (Stavudine) (stavudine) is peripheral neuropathy. Patients should be aware that peripheral neuropathy is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of Stavex (Stavudine) may be required if toxicity develops.

Caregivers of young children receiving Stavex (Stavudine) therapy should be instructed regarding detection and reporting of peripheral neuropathy.

17.5    Pancreatitis

Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of Stavex and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis.

The patient should be instructed to avoid alcohol while taking Stavex (Stavudine). Alcohol may increase the patient’s risk of pancreatitis or liver damage.

17.6    Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including Stavex (Stavudine). Patients receiving Stavex (Stavudine) should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/lipodystrophy.

Medication Guide

Stavex (Stavudine) ® (Zair-it)

(stavudine)

Stavex (Stavudine)® Capsules and

Stavex (Stavudine)® for Oral Solution

Read this Medication Guide before you start taking Stavex (Stavudine) 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 Stavex (Stavudine) before you start taking it and at regular check-ups. You should stay under your healthcare provider’s care when taking Stavex (Stavudine).

What is the most important information I should know about Stavex (Stavudine)?

Stavex (Stavudine) can cause serious side effects, including:

1. Build up of acid in your blood (lactic acidosis). Lactic acidosis can cause death and must be treated in the hospital. The risk of lactic acidosis may be higher if you:

  • have liver problems
  • are pregnant. There have been deaths reported in pregnant women who get lactic acidosis after taking Stavex (Stavudine) and VIDEX, or Stavex (Stavudine) and VIDEX EC (didanosine).
  • are female
  • are overweight
  • have been treated for a long time with other medicines used 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

2. Liver problems. Some people (including pregnant women) who have taken Stavex (Stavudine) have had serious liver problems. These problems include liver enlargement (hepatomegaly), fat in the liver (steatosis), liver failure, and death due to liver problems. Your healthcare provider should check your liver function while you are taking Stavex (Stavudine). You should be especially careful if you have a history of heavy alcohol use or liver problems. Use of Stavex (Stavudine) with VIDEX EC or VIDEX (didanosine) may increase your risk for liver damage.

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

3. Swelling of the pancreas (pancreatitis) that may cause death has occurred when Stavex (Stavudine) was used with VIDEX EC or VIDEX (didanosine). Pancreatitis can happen at any time during your treatment with Stavex (Stavudine).

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

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

What is Stavex (Stavudine)?

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

Stavex (Stavudine) will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking Stavex (Stavudine), 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 Stavex (Stavudine)?

Do not take Stavex (Stavudine) if you:

  • are allergic to Stavex (Stavudine) or any of the ingredients in Stavex (Stavudine). See the end of this Medication Guide for a complete list of the ingredients in Stavex (Stavudine).

What should I tell my healthcare provider before taking Stavex (Stavudine)?

Before you take Stavex (Stavudine), tell your healthcare provider if you:

  • have or had liver problems (such as hepatitis)
  • have or had problems with your pancreas (pancreatitis)
  • have or had kidney problems
  • have or had persistent numbness, tingling, or pain in the hands or feet (neuropathy)
  • have gallstones
  • drink alcoholic beverages
  • have any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if Stavex (Stavudine) will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking Stavex (Stavudine). You and your healthcare provider will decide if you should take Stavex (Stavudine) 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 healthcare provider about how you can take part in this registry.

  • are breastfeeding or plan to breastfeed. Do not breastfeed. It is not known if Stavex (Stavudine) 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 that you take, including prescription and non-prescription medicines, vitamins, or herbal supplements. Stavex (Stavudine) may affect the way other medicines work, and other medicines may affect how Stavex (Stavudine) works.

Especially tell your healthcare provider if you take:

  • COMBIVIR®, RETROVIR®, TRIZIVIR® (zidovudine or AZT)
  • VIDEX® or VIDEX EC® (didanosine)
  • ADRIAMYCIN®, RUBEX® (doxorubicin)
  • COPEGUS®, REBETOL®, RIBASPHERE®, RIBAVIRIN®, VIRAZOLE® (ribavirin)
  • ROFERON-A®, INTRON-A®, and others (interferon)
  • HYDREA®, DROXIA® (hydroxyurea)

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 Stavex (Stavudine)?

  • Take Stavex (Stavudine) exactly as your healthcare provider tells you to take it.
  • Your healthcare provider will tell you how much Stavex (Stavudine) to take and when to take it.
  • If your child will be taking Stavex (Stavudine), your child’s healthcare provider should give you instructions on how to give this medicine. If your child is taking Stavex (Stavudine) oral solution, shake the bottle well before measuring each dose.
  • Your healthcare provider may change your dose. Do not change your dose of Stavex (Stavudine) without talking to your healthcare provider.
  • Stavex (Stavudine) may be taken with or without food.
  • 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 may require your healthcare provider to monitor your therapy or change your therapy. 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 Stavex (Stavudine). Your healthcare provider may also lower your dosage of Stavex (Stavudine) if your kidneys are not working well.
  • If you take too much Stavex (Stavudine), contact a poison control center or emergency room right away.

What should I avoid while taking Stavex (Stavudine)?

  • Alcohol. You should avoid drinking alcohol while taking Stavex (Stavudine). 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 Stavex (Stavudine)?

Stavex (Stavudine) can cause serious side effects including:

  • Stavex (Stavudine) can cause lactic acidosis, liver problems, and pancreatitis. See “What is the most important information I should know about Stavex (Stavudine)?
  • Neurologic symptoms. Symptoms include: weakness of your legs, feet, arms, or hands (motor weakness) and numbness or tingling in your hands or feet (neuropathy). These problems can happen more often in people who have advanced HIV disease, have a history of peripheral neuropathy, or in people who take other medicines that also are associated with neuropathy including didanosine. In some cases, neuropathy may temporarily worsen after you stop taking Stavex (Stavudine). Neuropathy can be difficult to notice in children who take Stavex (Stavudine). Ask your child’s healthcare provider for the signs and symptoms of peripheral neuropathy in children.

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

  • numbness in your hands or feet
  • tingling in your hands or feet
  • weakness in your legs, feet, arms, or hands
  • Changes in body fat (fat redistribution). Changes in body fat (lipoatrophy or lipodystrophy) have been seen in some people taking HIV medicines including Stavex (Stavudine). Loss of body fat (lipoatrophy) happens more often in people who take Stavex (Stavudine) than in people who take other similar HIV medicines.
  • These changes may include:
    • more fat in or around your
      • trunk
      • upper back and neck (buffalo hump)
      • breast or chest
    • loss of fat in your
      • legs
      • arms
      • face

Your healthcare provider will monitor you for changes in your body fat. It is important to tell your healthcare provider if you notice any of these changes.

  • Changes in your immune system (immune reconstitution syndrome). Your immune system may begin to fight infections that have been 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.

The most common side effects of Stavex (Stavudine) include:

  • headache
  • diarrhea
  • rash
  • nausea
  • vomiting

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 Stavex (Stavudine). 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 Stavex (Stavudine)?

  • Capsules:
    • Store Stavex (Stavudine) capsules in a tightly closed container at room temperature at 59°F to 86°F (15°C to 30°C).
  • Oral solution:
    • Store Stavex (Stavudine) oral solution in the refrigerator at 36°F to 46°F (2°C to 8°C).
    • Store Stavex (Stavudine) oral solution in a tightly closed container.
    • Throw away any unused medicine after 30 days.

Keep Stavex (Stavudine) and all medicines out of the reach of children and pets.

General Information about the safe and effective use of Stavex (Stavudine)

If you have diabetes mellitus: Stavex (Stavudine) for Oral Solution contains 50 mg of sucrose (sugar) per mL.

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 Stavex (Stavudine) for a condition for which it was not prescribed. Do not give Stavex (Stavudine) 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 Stavex (Stavudine) in an unrecognizable closed container in the household trash.

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

What are the ingredients in Stavex (Stavudine)?

Active Ingredient: Stavex (Stavudine)

Inactive Ingredients:

Stavex (Stavudine) Capsules: microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate.

The gelatin shell contains: gelatin, titanium oxide, and iron oxide.

Stavex (Stavudine) for Oral Solution: methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming and flavoring agents.

Stavex (Stavudine)®, VIDEX®, VIDEX EC®, HYDREA®, and DROXIA® 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

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

1000007856 / 1349254

Rev December 2012

Stavex 15 mg Capsules Representative Packaging

See HOW SUPPLIED section for a complete list of available packages of Stavex (Stavudine).

60 Capsules       NDC 0003-1964-01

Stavex (Stavudine) ®

(stavudine)

Capsules

Rx only

15 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex 20 mg Capsules Representative Packaging

60 Capsules       NDC 0003-1965-01

Stavex (Stavudine) ®

(stavudine)

Capsules

Rx only

20 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex 30 mg Capsules Representative Packaging

60 Capsules       NDC 0003-1966-01

Stavex (Stavudine) ®

(stavudine)

Capsules

Rx only

30 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex 40 mg Capsules Representative Packaging

60 Capsules       NDC 0003-1967-01

Stavex (Stavudine) ®

(stavudine)

Capsules

Rx only

40 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex for Oral Solution Representative Packaging

200 mL       NDC 0003-1968-01

Stavex (Stavudine) ®

(stavudine)

for Oral Solution

Rx only

1 mg Stavex (Stavudine) per mL

when constituted per

label instructions

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex pharmaceutical active ingredients containing related brand and generic drugs:

infoActive 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.


Stavex available forms, composition, doses:

infoForm 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.


Stavex destination | category:

infoDestination 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.


Stavex Anatomical Therapeutic Chemical codes:

infoA 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.


Stavex pharmaceutical companies:

infoPharmaceutical 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."ZERIT (STAVUDINE) CAPSULE, GELATIN COATED ZERIT (STAVUDINE) CAPSULE, GELATIN COATED ZERIT (STAVUDINE) POWDER, FOR SOLUTION [E.R. SQUIBB & SONS, L.L.C.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."LAMIVUDINE TABLET, FILM COATED [APOTEX CORP.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."STAVUDINE: 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).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Stavex?

Depending on the reaction of the Stavex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Stavex 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 Stavex 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 Stavex, 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 Stavex 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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