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ZERIT
Overview
What is ZERIT?
ZERIT is the brand name for stavudine (d4T), a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV).
ZERIT (stavudine) Capsules are supplied for oral administration in strengths of 15, 20, 30, and 40 mg of 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.
ZERIT (stavudine) for Oral Solution is supplied as a dye-free, fruit-flavored powder in bottles with child-resistant closures providing 200 mL of a 1 mg/mL stavudine 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.
The chemical name for stavudine is 2',3'-didehydro-3'-deoxythymidine. Stavudine has the following structural formula:
Stavudine is a white to off-white crystalline solid with the molecular formula CHNO and a molecular weight of 224.2. The solubility of 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 stavudine at 23° C is 0.144.
What does ZERIT look like?
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What are the available doses of ZERIT?
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What should I talk to my health care provider before I take ZERIT?
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How should I use ZERIT?
ZERIT (stavudine), in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection (see ).
The interval between doses of ZERIT (stavudine) should be 12 hours. ZERIT may be taken with or without food.
Adults:
40 mg twice daily for patients ≥60 kg.
30 mg twice daily for patients <60 kg.
Pediatrics:
What interacts with ZERIT?
ZERIT is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.
What are the warnings of ZERIT?
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 stavudine and other antiretrovirals.
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 ) 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).
2. Hepatic Impairment and Toxicity:
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.
An increased risk of hepatotoxicity may occur in patients treated with ZERIT in combination with didanosine and hydroxyurea compared to when ZERIT is used alone. Deaths attributed to hepatotoxicity have occurred in patients receiving this combination. This combination should be avoided.
Use with Interferon and Ribavirin-Based Regimens
In vitro
CLINICAL PHARMACOLOGY:
hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon and ribavirin
the complete prescribing information for interferon and ribavirin
3. Neurologic Symptoms:
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-Barré syndrome (including respiratory failure). Symptoms may continue or worsen following discontinuation of therapy.
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving ZERIT therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, with a history of neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine (see ).
4. Pancreatitis:
Fatal and nonfatal pancreatitis have occurred during therapy when ZERIT 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 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. The new regimen should not contain didanosine.
What are the precautions of ZERIT?
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
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 infection, cytomegalovirus, pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.
Information for Patients (See Patient Information Leaflet.)
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 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 disease or a history of peripheral neuropathy, and that dose modification and/or 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 when ZERIT is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when ZERIT is used alone. An increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of ZERIT and didanosine. Patients treated with this combination should be closely monitored for symptoms of pancreatitis. 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 ZERIT (stavudine) is not a cure for HIV infection, and that they may continue to acquire illnesses associated with HIV infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using ZERIT. They should be advised that ZERIT therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of ZERIT are unknown at this time.
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 should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Patients should be advised of the importance of adherence to any antiretroviral regimen, including those that contain ZERIT.
Drug Interactions (see also CLINICAL PHARMACOLOGY)
Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT should be avoided.
In vitro
in vitro
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, reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation. Stavudine produced positive results in the human lymphocyte clastogenesis and mouse fibroblast assays, and in the mouse micronucleus test. In the 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 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 C) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.
Pregnancy
Pregnancy Category C
Reproduction studies have been performed in rats and rabbits with exposures (based on C) 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 ). 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:
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
mothers should be instructed not to breast-feed if they are receiving ZERIT
Pediatric Use
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.
Adverse events 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-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-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens (see , ).
Geriatric Use
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 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 ).
What are the side effects of ZERIT?
Adults
Fatal lactic acidosis has occurred in patients treated with ZERIT in combination with other antiretroviral agents. Patients with suspected lactic acidosis should immediately suspend therapy with ZERIT. Permanent discontinuation of ZERIT should be considered for patients with confirmed lactic acidosis.
ZERIT therapy has rarely been associated with motor weakness, occurring predominantly in the setting of lactic acidosis. If motor weakness develops, ZERIT should be discontinued.
ZERIT therapy has also been associated with peripheral sensory neuropathy, which can be severe, is dose related, and occurs more frequently in patients being treated with other drugs that have been associated with neuropathy (including didanosine), in patients with advanced HIV infection, or in patients who have previously experienced peripheral neuropathy.
Patients should be monitored for the development of neuropathy, which is usually manifested by numbness, tingling, or pain in the feet or hands. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy. If symptoms resolve completely, patients may tolerate resumption of treatment at one-half the dose (see ). If neuropathy recurs after resumption, permanent discontinuation of ZERIT should be considered.
Selected clinical adverse events that occurred in adult patients receiving ZERIT (stavudine) in a controlled monotherapy study (Study AI455-019) are provided in .
Pancreatitis was observed in 3 of the 412 adult patients who received ZERIT in a controlled monotherapy study.
Selected clinical adverse events that occurred in antiretroviral-naive adult patients receiving ZERIT from two controlled combination studies are provided in .
Pancreatitis resulting in death was observed in patients treated with ZERIT plus didanosine in controlled clinical studies and in postmarketing reports.
Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455‑019) are provided in .
Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables and .
| a | ||||
| b | ||||
| Adverse Events | ZERIT (40 mg twice daily)(n=412) | zidovudine(200 mg 3 times daily)(n=402) | ||
| Headache | 54 | 49 | ||
| Diarrhea | 50 | 44 | ||
| Peripheral Neurologic Symptoms/Neuropathy | 52 | 39 | ||
| Rash | 40 | 35 | ||
| Nausea and Vomiting | 39 | 44 | ||
| a | ||||
| b | ||||
| c | ||||
| START 1 | START 2 | |||
|---|---|---|---|---|
| Adverse Events | ZERIT + lamivudine +indinavir(n=100) | zidovudine + lamivudine + indinavir(n=102) | ZERIT + didanosine + indinavir(n=102) | zidovudine + lamivudine + indinavir(n=103) |
| 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 NeurologicSymptoms/ Neuropathy | 8 | 7 | 21 | 10 |
| a | ||||
| b | ||||
| ULN = upper limit of normal. | ||||
| Parameter | ZERIT(40 mg twice daily)(n=412) | zidovudine(200 mg 3 times daily)(n=402) | ||
| AST (SGOT) (>5.0 x ULN) | 11 | 10 | ||
| ALT (SGPT) (>5.0 x ULN) | 13 | 11 | ||
| Amylase (≥1.4 x ULN) | 14 | 13 | ||
| ULN = upper limit of normal. | ||||
| START 1 | START 2 | |||
| Parameter | ZERIT + lamivudine + indinavir(n=100) | zidovudine + lamivudine + indinavir (n=102) | ZERIT + didanosine + indinavir (n=102) | zidovudine + lamivudine + indinavir(n=103) |
| Bilirubin (>2.6 x ULN) | 7 | 6 | 16 | 8 |
| AST (SGOT) (>5 x ULN) | 5 | 2 | 7 | 7 |
| ALT (SGPT) (>5 x ULN) | 6 | 2 | 8 | 5 |
| GGT (>5 x ULN) | 2 | 2 | 5 | 2 |
| Lipase (>2 x ULN) | 6 | 3 | 5 | 5 |
| Amylase (>2 x ULN) | 4 | <1 | 8 | 2 |
| START 1 | START 2 | |||
| Parameter | ZERIT + lamivudine + indinavir (n=100) | zidovudine + lamivudine + indinavir (n=102) | ZERIT + 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 |
Observed During Clinical Practice
The following events have been identified during post-approval use of ZERIT (stavudine). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events 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
Digestive Disorders
Exocrine Gland Disorders
Hematologic Disorders
Liver
Metabolic Disorders
Musculoskeletal
Nervous System
Use with Didanosine- and Hydroxyurea-Based Regimens
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 didanosine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy. The combination of ZERIT and hydroxyurea, with or without didanosine, should be avoided (see and ).
Pediatric Patients
Adverse reactions and serious laboratory abnormalities in pediatric patients from birth through adolescence were similar in type and frequency to those seen in adult patients (see ).
What should I look out for while using ZERIT?
ZERIT is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.
What might happen if I take too much ZERIT?
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. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied.
How should I store and handle ZERIT?
ZERIT 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 (see USP Controlled Room Temperature). ZERIT 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 (see USP Controlled Room Temperature). After constitution, store tightly closed containers of ZERIT for Oral Solution in a refrigerator, 2° C to 8° C (36° F to 46° F). Discard any unused portion after 30 days. ZERIT 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 (see USP Controlled Room Temperature). ZERIT 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 (see USP Controlled Room Temperature). After constitution, store tightly closed containers of ZERIT for Oral Solution in a refrigerator, 2° C to 8° C (36° F to 46° F). Discard any unused portion after 30 days. ZERIT (stavudine) Capsules are supplied by as follows:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
The pharmacokinetics of stavudine have been evaluated in HIV-infected adult and pediatric patients (Tables-). Peak plasma concentrations (C) 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 stavudine with repeated administration every 6, 8, or 12 hours.
Non-Clinical Toxicology
ZERIT is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT should be avoided.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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