Side Effects of Zerit (stavudine)

Zerit (stavudine) is a type of antiviral medication called a reverse transcriptase inhibitor used to treat infections with the human immunodeficiency virus (HIV). 

During infection with HIV, the HIV virus multiplies within the body's cells. The newly formed viruses are released from the cells and spread throughout the body where they infect other cells. When producing new viruses, the HIV virus must manufacture new DNA for each virus. 

Reverse transcriptase is the enzyme that the virus uses to form this new DNA. 

Specifically, Zerit is converted within the body to its active form (stavudine triphosphate). This active form is similar to thymidine triphosphate, a chemical used by the HIV virus to make new DNA. The reverse transcriptase uses stavudine triphosphate instead of thymidine triphosphate for making DNA, and the stavudine triphosphate interferes with the action of the reverse transcriptase. Stavudine does not kill existing HIV virus, and it is not a cure for HIV.

Common side effects of Zerit include:

• chills,
• rash,
• abdominal pain,
• weight loss, and
• insomnia.

Serious side effects of Zerit include:

• a decrease in blood cells,
• muscle pain,
• pancreatitis,
• liver failure,
• metabolic disturbance (lactic acidosis), and
• severe peripheral neuropathy, a condition in which sensation in the legs and/or arms is altered or lost.
  • Symptoms of peripheral neuropathy are tingling and numbness and pain in the feet or hands.

Drug interactions of Zerit include hydroxyurea.

Tell your doctor if you are pregnant, and use prescribed medications to control infection. HIV can be passed to the baby if the virus is not controlled during pregnancy. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to Zerit during pregnancy.

It is unknown if Zerit is excreted in breast milk. HIV infected mothers should not breastfeed because of the potential risk of transmitting HIV to an infant that is not infected.

The most severe side effects are:

• a decrease in blood cells,
• muscle pain (myopathy),
• pancreatitis (inflammation of the pancreas),
• liver failure, and
• metabolic disturbance (lactic acidosis).

Stavudine damages nerves and can cause a severe peripheral neuropathy, a condition in which sensation in the legs and/or arms is altered or lost. Symptoms of peripheral neuropathy are tingling, numbness and pain in the feet or hands.

Other side effects include

• chills,
• rash,
• abdominal pain,
• weight loss and
• insomnia.

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

• lactic acidosis and severe hepatomegaly with steatosis
• hepatic toxicity
• neurologic symptoms and motor weakness
• pancreatitis
• lipoatrophy

When Zerit is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when stavudine is used alone.

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 clinical practice.

Clinical Trials Experience In Adults

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

Table 2: Selected Adverse Reactions in Study AI455-019^a (Monotherapy)

Pancreatitis was observed in 3 of the 412 adult patients who received Zerit in study AI455-019.

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

Table 3: Selected Adverse Reactions^a in START 1 and START 2^b Studies (Combination Therapy)

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

Table 4: Selected Laboratory Abnormalities in Study AI455-019^a,b

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

Table 5: Selected Laboratory Abnormalities in START 1 and START 2 Studies (Grades 3-4)

Table 6: Selected Laboratory Abnormalities in START 1 and START 2 Studies (All Grades)

Clinical Trials 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.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of Zerit. 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 Zerit, or a combination of these factors.

Body as a Whole: abdominal pain, allergic reaction, chills/fever.

Digestive Disorders: anorexia.

Exocrine Gland Disorders: pancreatitis, including fatal cases.

Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis.

Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis, hepatitis and liver failure.

Metabolic Disorders: lipoatrophy, diabetes mellitus and hyperglycemia.

Musculoskeletal: myalgia.

Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis).

Zerit is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.

Hydroxyurea

When stavudine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when stavudine is used alone. Thus, patients treated with Zerit in combination with hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy. The combination of Zerit and hydroxyurea should be avoided.

Zidovudine

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

Doxorubicin

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

Ribavirin

In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. The clinical significance of the interaction with stavudine is unknown; therefore, concomitant use of 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), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients.