"The US Food and Drug Administration has expanded the use of the protease inhibitor darunavir (Prezista, Janssen Therapeutics) to pregnant women with HIV infection, the company announced.
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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 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 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 stavudine and didanosine with other antiretroviral agents. The combination of 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].
Particular caution should be exercised when administering ZERIT 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 Neurologic Symptoms below] might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.
Treatment with ZERIT (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 ZERIT should be considered for patients with confirmed lactic acidosis.
The safety and efficacy of ZERIT have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. [See ADVERSE REACTIONS]
Use with Interferon and Ribavirin-Based Regimens
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as 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 stavudine in HIV-1/HCV co-infected patients [see DRUG INTERACTIONS], 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 stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of 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).
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including ZERIT. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barre syndrome (including respiratory failure). If motor weakness develops, ZERIT 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 ZERIT 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].
Patients should be monitored for the development of peripheral neuropathy. Stavudinerelated peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of ZERIT should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy.
Fatal and nonfatal pancreatitis have occurred during therapy when ZERIT was part of a combination regimen that included didanosine in both treatment-naive and treatmentexperienced patients, regardless of degree of immunosuppression. The combination of ZERIT and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of ZERIT after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine.
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.
In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with 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 stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving ZERIT 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 ZERIT including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ZERIT. 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-Barre 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.
Patient Counseling Information
See MEDICATION GUIDE.
Patients should be advised that ZERIT 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 ZERIT and the importance of adherence to any antiretroviral regimen including those that contain ZERIT.
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 ZERIT 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 ZERIT is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when ZERIT 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 ZERIT, 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 ZERIT for Oral Solution contains 50 mg of sucrose (sugar) per mL.
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 ZERIT therapy may be required.
Patients should be informed that an increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with ZERIT in combination with didanosine and hydroxyurea. This combination should be avoided.
Patients should be informed that an important toxicity of ZERIT (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 ZERIT may be required if toxicity develops.
Caregivers of young children receiving ZERIT therapy should be instructed regarding detection and reporting of peripheral neuropathy.
Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of ZERIT 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 ZERIT. Alcohol may increase the patient's risk of pancreatitis or liver damage.
Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including ZERIT. Patients receiving ZERIT should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/ lipodystrophy.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In 2-year carcinogenicity studies in mice and rats, 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.
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. 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, 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, stavudine was clastogenic in bone marrow cells following oral 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.
Use In Specific Populations
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 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 stavudine in pregnant women. 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 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]. The combination of 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 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 stavudine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine is excreted in human milk, there exists the potential for adverse effects from 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 ZERIT.
Use of stavudine in pediatric patients from birth through adolescence is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].
Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of stavudine in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received ZERIT 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received ZERIT 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 ZERIT 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.
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, Table 9)].
Clinical studies of ZERIT (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 ZERIT 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.
ZERIT 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].
Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the ZERIT dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/2/2016
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