DRUGS & SUPPLEMENTS
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS
Hematologic Toxicity: T-ZA tablets have been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced HIV-1 disease .
Myopathy: Prolonged use of T-ZA has been associated with symptomatic myopathy .
Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including T-ZA and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur .
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
1 INDICATIONS AND USAGE
T-ZA is a nucleoside analogue reverse transcriptase inhibitor indicated for:
1.1 Treatment of HIV-1
T-ZA tablets USP, a nucleoside reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
1.2 Prevention of Maternal-Fetal HIV-1 Transmission
T-ZA tablets USP are indicated for the prevention of maternal-fetal HIV-1 transmission . The indication is based on a dosing regimen that included three components:
Points to consider prior to initiating T-ZA tablets USP in pregnant women for the prevention of maternal-fetal HIV-1 transmission include:
2 DOSAGE AND ADMINISTRATION
2.1 Adults – Treatment of HIV-1 Infection
The recommended oral dose of T-ZA tablets is 300 mg twice daily in combination with other antiretroviral agents.
2.2 Pediatric Patients
Healthcare professionals should pay special attention to accurate calculation of the dose of T-ZA tablets, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors.
Prescribers should calculate the appropriate dose of T-ZA tablets for each child based on body weight (kg) and should not exceed the recommended adult dose.
Before prescribing T-ZA tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a T-ZA tablet, the T-ZA syrup formulation should be prescribed.
The recommended oral dosage in pediatric patients aged 4 weeks to less than 18 years and weighing greater than or equal to 4 kg is provided in Table 1. T-ZA syrup should be used to provide accurate dosage when whole tablets are not appropriate.
Alternatively, dosing for T-ZA tablets can be based on body surface area (BSA) for each child. The recommended oral dose of T-ZA tablets is 480 mg per m 2 per day in divided doses (240 mg per m 2 twice daily or 160 mg per m 2 three times daily). In some cases the dose calculated by mg per kg will not be the same as that calculated by BSA.
2.3 Prevention of Maternal-Fetal HIV-1 Transmission
The recommended dosage regimen for administration to pregnant women and their neonates is:
100 mg orally 5 times per day until the start of labor . During labor and delivery, intravenous T-ZA should be administered at 2 mg per kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg per kg per hour (total body weight) until clamping of the umbilical cord.
Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates unable to receive oral dosing may be administered T-ZA intravenously. See Table 2.
2.4 Patients with Severe Anemia and/or Neutropenia
Significant anemia and/or significant neutropenia (granulocyte count less than 750 cells per mm 3 or reduction greater than 50% from baseline) may require a dose interruption until evidence of marrow recovery is observed . In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoietin level and patient tolerance.
2.5 Patients with Renal Impairment
In patients maintained on hemodialysis or peritoneal dialysis or with creatinine clearance (CrCl) by Cockcroft-Gault less than 15 mL per min, the recommended oral dosage is 100 mg every 6 to 8 hours .
2.6 Patients with Hepatic Impairment
There are insufficient data to recommend dose adjustment of T-ZA tablets in patients with impaired hepatic function or liver cirrhosis. Frequent monitoring of hematologic toxicities is advised .
3 DOSAGE FORMS AND STRENGTHS
T-ZA Tablets USP, 300 mg are white, biconvex, round, film-coated tablets debossed with "S2" on one side and blank on the other side.
Tablets: 300 mg ( 3)
T-ZA tablets are contraindicated in patients who have had a potentially life-threatening hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the formulations.
Hypersensitivity to T-ZA or any of the components (e.g., anaphylaxis, Stevens-Johnson syndrome). ( 4)
5 WARNINGS AND PRECAUTIONS
5.1 Hematologic Toxicity/Bone Marrow Suppression
T-ZA tablets should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm 3 or hemoglobin less than 9.5 g per dL. Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the most significant adverse events observed. In patients who experience hematologic toxicity, a reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks. There have been reports of pancytopenia associated with the use of T-ZA, which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of T-ZA, and/or blood transfusions, has occurred during treatment with T-ZA alone or in combination with other antiretrovirals.
Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who are treated with T-ZA. For HIV-1-infected individuals and patients with asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage interruption may be needed .
Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of T-ZA.
5.4 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 T-ZA and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering T-ZA to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with T-ZA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
5.5 Use with Interferon- and Ribavirin-based Regimens in HIV-1/HCV Co-infected Patients
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as T-ZA. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with T-ZA in HIV-1/HCV co-infected subjects , exacerbation of anemia due to ribavirin has been reported when T-ZA is part of the HIV regimen. Coadministration of ribavirin and T-ZA is not advised. Consideration should be given to replacing T-ZA in established combination HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and T-ZA should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia.
Discontinuation of T-ZA should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6).
5.6 Use with Other Zidovudine-containing Products
T-ZA tablets should not be administered with combination products that contain T-ZA as one of their components.
5.7 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including T-ZA. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.8 Fat Redistribution
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance”, have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-800-325-9994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The frequency and severity of adverse reactions associated with the use of T-ZA are greater in patients with more advanced infection at the time of initiation of therapy.
Table 3 summarizes adverse reactions reported at a statistically significant greater incidence for subjects receiving oral T-ZA in a monotherapy trial.
In addition to the adverse reactions listed in Table 3, adverse reactions observed at an incidence of greater than or equal to 5% in any treatment arm in clinical trials (NUCA3001, NUCA3002, NUCB3001 and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in these trials hyperbilirubinemia was reported at an incidence of less than or equal to 0.8%.
Selected laboratory abnormalities observed during a clinical trial of monotherapy with oral T-ZA are shown in Table 4.
The clinical adverse reactions reported among adult recipients of T-ZA may also occur in pediatric patients.
Trial ACTG 300: Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with EPIVIR ® (lamivudine) oral suspension 4 mg per kg twice daily plus T-ZA 160 mg per m 2 3 times daily compared with didanosine in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.
Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.
Macrocytosis was reported in the majority of pediatric subjects receiving T-ZA 180 mg per m 2 every 6 hours in open-label trials. Additionally, adverse reactions reported at an incidence of less than 6% in these trials were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.
Use for the Prevention of Maternal-Fetal Transmission of HIV-1
In a randomized, double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to determine the utility of T-ZA for the prevention of maternal-fetal HIV-1 transmission, T-ZA syrup at 2 mg per kg was administered every 6 hours for 6 weeks to neonates beginning within 12 hours following birth. The most commonly reported adverse reactions were anemia and neutropenia (less than 1,000 cells per mm 3). Anemia occurred in 22% of the neonates who received T-ZA and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1 g per dL for neonates receiving T-ZA compared with neonates receiving placebo. No neonates with anemia required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with T-ZA. Neutropenia in neonates was reported with similar frequency in the group that received T-ZA (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to T-ZA are unknown.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postmarketing use of T-ZA. 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.
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/
accumulation of body fat .
Cardiovascular: Cardiomyopathy, syncope.
Eye: Macular edema.
Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hematologic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
Hepatobiliary: Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis, tremor.
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.
Reproductive System and Breast: Gynecomastia.
Respiratory: Dyspnea, rhinitis, sinusitis.
Skin and Subcutaneous Tissue: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweating, urticaria.
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
Renal and Urinary: Urinary frequency, urinary hesitancy.
7 DRUG INTERACTIONS
7.1 Antiretroviral Agents
Concomitant use of T-ZA with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro.
Nucleoside Analogues Affecting DNA Replication
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of T-ZA against HIV-1; concomitant use of such drugs should be avoided.
Concomitant use of T-ZA with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro.
7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of T-ZA.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C
In humans, treatment with T-ZA during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with T-ZA . There were no differences in pregnancy-related adverse events between the treatment groups. Animal reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations.
A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of T-ZA for the prevention of maternal-fetal HIV-1-transmission . Congenital abnormalities occurred with similar frequency between neonates born to mothers who received T-ZA and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.
Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of T-ZA that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100 mg dose of T-ZA. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received T-ZA up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg per day T-ZA). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose .
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to T-ZA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
8.3 Nursing Mothers
T-ZA is excreted in human milk. After administration of a single dose of 200 mg T-ZA to 13 HIV-1-infected women, the mean concentration of T-ZA was similar in human milk and serum.
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving T-ZA.
8.4 Pediatric Use
T-ZA has been studied in HIV-1-infected pediatric subjects aged at least 6 weeks who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. T-ZA has also been studied in neonates perinatally exposed to HIV-1 .
8.5 Geriatric Use
Clinical studies of T-ZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Renal Impairment
Unchanged T-ZA and its glucuronide metabolite are primarily eliminated from the body by renal excretion. In patients with severely impaired renal function (CrCl less than 15 mL per min), dosage reduction is recommended .
8.7 Hepatic Impairment
T-ZA is primarily eliminated by hepatic metabolism and T-ZA concentrations appear to be increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised. There are insufficient data to recommend dose adjustment of T-ZA in patients with impaired hepatic function or liver cirrhosis .
Acute overdoses of T-ZA have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with T-ZA apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of T-ZA while elimination of its primary metabolite, 3ʹ‑azido-3ʹ-deoxy-5ʹ- O-β- D-glucopyranuronosylthymidine (GZDV), is enhanced. If overdose occurs, the patient should be monitored for evidence of toxicity and given standard supportive treatment as required.
T-ZA (formerly called azidothymidine [AZT]), is a pyrimidine nucleoside analogue active against HIV-1. The chemical name of T-ZA is 3ʹ-Azido-3ʹ-deoxythymidine; it has the following structural formula:
T-ZA is a white to yellowish powder with a molecular weight of 267.24 and a solubility of 20.1 mg per mL in water at 25°C. The molecular formula is C 10H 13N 5O 4.
T-ZA tablets USP are for oral administration. Each film-coated tablet contains 300 mg of T-ZA and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, polyethylene glycol, titanium dioxide, polyvinyl alcohol-part hydrolyzed, talc and lecithin soya.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
T-ZA is an antiviral agent .
Absorption and Bioavailability
In adults, following oral administration, T-ZA is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when T-ZA was administered as T-ZA tablets or syrup compared with T-ZA capsules. The pharmacokinetic properties of T-ZA in fasting adult subjects are summarized in Table 7.
The apparent volume of distribution of T-ZA is 1.6 ± 0.6 L per kg (Table 7); and binding to plasma protein is low (less than 38%).
Metabolism and Elimination
T-ZA is primarily eliminated by hepatic metabolism. The major metabolite of T-ZA is GZDV. GZDV AUC is about 3-fold greater than the T-ZA AUC. Urinary recovery of T-ZA and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration and 18% and 60%, respectively, following IV dosing. A second metabolite, 3ʹ-amino-3ʹ‑deoxythymidine, has been identified in the plasma following single-dose IV administration of T-ZA. The AMT AUC was one-fifth of the T-ZA AUC. Pharmacokinetics of T-ZA were dose independent at oral dosing regimens ranging from 2 mg per kg every 8 hours to 10 mg per kg every 4 hours.
Effect of Food on Absorption
T-ZA may be administered with or without food. The T-ZA AUC was similar when a single dose of T-ZA was administered with food.
Renal Impairment: T-ZA clearance was decreased resulting in increased T-ZA and GZDV half-life and AUC in subjects with impaired renal function following a single 200-mg oral dose (Table 8). Plasma concentrations of AMT were not determined. No dose adjustment is recommended for patients with CrCl greater than or equal to 15 mL per min.
Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of T-ZA were evaluated in a multiple-dose trial in subjects undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating oral doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent T-ZA oral clearance was approximately 50% of that reported in subjects with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of T-ZA, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis .
Hepatic Impairment: Data describing the effect of hepatic impairment on the pharmacokinetics of T-ZA are limited. However, T-ZA is eliminated primarily by hepatic metabolism and it appears that T-ZA clearance is decreased and plasma concentrations are increased in subjects with hepatic impairment. There are insufficient data to recommend dose adjustment of T-ZA in patients with impaired hepatic function or liver cirrhosis .
Pediatric Patients: T-ZA pharmacokinetics have been evaluated in HIV-1-infected pediatric subjects (Table 9).
Patients Aged 3 Months to 12 Years: Overall, T-ZA pharmacokinetics in pediatric patients older than 3 months are similar to those in adult patients. Proportional increases in plasma T-ZA concentrations were observed following administration of oral solution from 90 to 240 mg per m 2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult subjects, the major route of elimination was by metabolism to GZDV. After IV dosing, about 29% of the dose was excreted in the urine unchanged, and about 45% of the dose was excreted as GZDV .
Patients Aged Less Than 3 Months T-ZA pharmacokinetics have been evaluated in pediatric subjects from birth to 3 months of life. T-ZA elimination was determined immediately following birth in eight neonates who were exposed to T-ZA in utero. The half-life was 13 ± 5.8 hours. In neonates less than or equal to 14 days, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric subjects older than 14 days. For dose recommendations for neonates .
Pregnancy: T-ZA pharmacokinetics have been studied in a Phase I trial of eight women during the last trimester of pregnancy. T-ZA pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, T-ZA concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery .
Although data are limited, methadone maintenance therapy in five pregnant women did not appear to alter T-ZA pharmacokinetics.
Geriatric Patients: T-ZA pharmacokinetics have not been studied in subjects over 65 years of age.
Gender: A pharmacokinetic trial in healthy male (n = 12) and female (n = 12) subjects showed no differences in T-ZA AUC when a single dose of T-ZA was administered as the
300 mg T-ZA tablet.
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving T-ZA, while in one case a high level was documented. However, in a pharmacokinetic interaction trial in which 12 HIV-1-positive volunteers received a single 300-mg phenytoin dose alone and during steady-state T-ZA conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally assess the effect of phenytoin on T-ZA kinetics, a 30% decrease in oral T-ZA clearance was observed with phenytoin.
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and T-ZA. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or T-ZA (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects .
Mechanism of Action
T-ZA is a synthetic nucleoside analogue. Intracellularly, T-ZA is phosphorylated to its active 5ʹ-triphosphate metabolite, T-ZA triphosphate. The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.
The antiviral activity of T-ZA against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC 50 and EC 90 values for T-ZA were 0.01 to 0.49 µM (1 µM = 0.27 mcg per mL) and 0.1 to 9 µM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with resistance gave median EC 50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92 baseline samples from COL40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC 50 values of T-ZA against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from 0.00049 to 0.004 µM. In cell culture drug combination studies, T-ZA demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of T-ZA in cell culture.
Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed mutations in the HIV-1 RT gene resulting in six amino acid substitutions that confer T-ZA resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to T-ZA was restored by 12 weeks of treatment with lamivudine and T-ZA. Combination therapy with lamivudine plus T-ZA delayed the emergence of substitutions conferring resistance to T-ZA.
In a trial of 167 HIV-1-infected subjects, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and T-ZA were recovered from subjects treated for at least 1 year with T-ZA plus didanosine or T-ZA plus zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with T-ZA monotherapy, with the Q151M substitution being most commonly associated with multi-drug resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and T-ZA. Thymidine analogue mutations (TAMs) are selected by T-ZA and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
T-ZA was administered orally at three dosage levels to separate groups of mice and rats. Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.
In mice, seven late-appearing (after 19 months) vaginal neoplasms (five nonmetastasizing squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
In rats, two late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Two transplacental carcinogenicity studies were conducted in mice. One study administered T-ZA at doses of 20 mg per kg per day or 40 mg per kg per day from gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of T-ZA administered in this study produced T-ZA exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered T-ZA at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from Days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of T-ZA.
T-ZA was mutagenic in a 5178Y/TK +/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.
Impairment of Fertility
T-ZA, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area, had no effect on fertility judged by conception rates.
13.2 Animal Toxicology and/or Pharmacology
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg per kg per day revealed no evidence of teratogenicity with T-ZA. T-ZA treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology studies resulted in peak T-ZA plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, T-ZA exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3000 mg per kg per day (very near the oral median lethal dose in rats of 3683 mg per kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak T-ZA plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less.
14 CLINICAL STUDIES
Therapy with T-ZA has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV-1 disease and to delay disease progression in asymptomatic HIV-1-infected patients.
T-ZA in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA.
The clinical efficacy of a combination regimen that includes T-ZA was demonstrated in trial ACTG 320. This trial was a multi-center, randomized, double-blind, placebo-controlled trial that compared T-ZA 600 mg per day plus EPIVIR 300 mg per day to T-ZA plus EPIVIR plus indinavir 800 mg three times daily. The incidence of AIDS-defining events or death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm.
In controlled trials of treatment-naive subjects conducted between 1986 and 1989, monotherapy with T-ZA, as compared with placebo, reduced the risk of HIV-1 disease progression, as assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining events, or death. These trials enrolled subjects with advanced disease (BW 002), and asymptomatic or mildly symptomatic disease in subjects with CD4+ cell counts between 200 and 500 cells per mm 3 (ACTG 016 and ACTG 019). A survival benefit for monotherapy with T-ZA was not demonstrated in the latter two trials. Subsequent trials showed that the clinical benefit of monotherapy with T-ZA was time limited.
14.2 Pediatric Patients
ACTG 300 was a multi-center, randomized, double-blind trial that provided for comparison of EPIVIR plus T-ZA to didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive pediatric subjects were enrolled in these two treatment arms. The median age was 2.7 years, the mean baseline CD4+ cell count was 868 cells per mm 3, and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies per mL. The median duration that subjects remained on trial was approximately 10 months. Results are summarized in Table 11.
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
The utility of T-ZA for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells per mm 3 (median in the treated group: 560 cells per mm 3) who had little or no previous exposure to T-ZA. Oral T-ZA was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of T-ZA during labor and delivery. Following birth, neonates received oral T-ZA syrup for 6 weeks. The trial showed a statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving T-ZA and the group receiving placebo. Of 363 neonates evaluated in the trial, the estimated risk of HIV-1 infection was 7.8% in the group receiving T-ZA and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. T-ZA was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.
16 HOW SUPPLIED/STORAGE AND HANDLING
T-ZA Tablets USP, 300 mg are supplied as white, biconvex, round, film-coated tablets containing 300 mg of T-ZA per tablet. Each tablet has one side debossed with “S2” and blank on the other side.
Bottles of 60 (NDC 0527-1905-06).
Store at 20° to 25°C (68° to 77°F).
17 PATIENT COUNSELING INFORMATION
Inform patients that potentially life-threatening hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) can occur while receiving T-ZA. Instruct patients to immediately contact their healthcare provider if they develop rash, as it may be a sign of a more serious reaction. Advise patients that it is very important that they remain under a healthcare provider’s care during treatment with T-ZA.
Neutropenia and Anemia
Inform patients that the major toxicities of T-ZA are neutropenia and/or anemia. The frequency and severity of these toxicities are greater in patients with more advanced disease and in those who initiate therapy later in the course of their infection. Advise patients that if toxicity develops, they may require transfusions or drug discontinuation. Advise patients of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced symptomatic HIV-1 disease .
Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of T-ZA .
Inform patients that some HIV medicines, including T-ZA, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) .
Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin .
Use with Other Zidovudine-containing Products
T-ZA tablets should not be administered with combination products that contain T-ZA as one of their components (e.g., COMBIVIR [lamivudine and zidovudine] tablets or TRIZIVIR [abacavir sulfate, lamivudine, and zidovudine] tablets) .
Immune Reconstitution Syndrome
In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection .
Redistribution/Accumulation of Body Fat:
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time .
Common Adverse Reactions:
Inform patients that the most commonly reported adverse reactions in adult patients being treated with T-ZA were headache, malaise, nausea, anorexia, and vomiting. The most commonly reported adverse reactions in pediatric patients receiving T-ZA were fever, cough, and digestive disorders. Patients also should be encouraged to contact their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being treated with T-ZA .
Caution patients about the use of other medications, including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of T-ZA .
Inform pregnant women considering the use of T-ZA during pregnancy for prevention of HIV-1 transmission to their infants that transmission may still occur in some cases despite therapy. The long-term consequences of in utero and infant exposure to T-ZA are unknown, including the possible risk of cancer .
Advise HIV-1-infected pregnant women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected .
Information About HIV-1 Infection
T-ZA is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-1-related illness. Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician when using T-ZA tablets.
Patients should be informed to take all HIV medications exactly as prescribed.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
Instruct patients that if they miss a dose, they should just take their next dose at the usual time. Patients should not double their next dose.
COMBIVIR, EPIVIR, and TRIZIVIR are registered trademarks of the ViiV Healthcare group of companies.
Sunshine Lake Pharma Co., Ltd.
Guangdong Province 523808
Lannett Company, Inc.
Philadelphia, PA 19136
Revised: 12/2015, Revision 1
PRINCIPAL DISPLAY PANEL – 300 mg
Each tablet contains 300 mg of T-ZA.
Dosage: See package insert for Dosage and Administration.
Store at 20° to 25°C (68° to 77°F). Preserve in tight, light-resistant containers.
Lannett Company, Inc.
Sunshine Lake Pharma Co., Ltd.
Guangdong Province, China
Rev. 12/13 10-002
T-ZA pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
T-ZA available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
T-ZA destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
T-ZA Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
T-ZA pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming T-ZA?
Depending on the reaction of the T-ZA after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider T-ZA 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 T-ZA 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.
Reviewsdrugs.com conducted a study on T-ZA, 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 T-ZA 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.
Visitor reported usefulNo survey data has been collected yet
Visitor reported side effectsNo survey data has been collected yet
Visitor reported price estimatesNo survey data has been collected yet
Visitor reported frequency of useNo survey data has been collected yet
Visitor reported dosesNo survey data has been collected yet
Visitor reported time for resultsNo survey data has been collected yet
Visitor reported administrationNo survey data has been collected yet
Visitor reported ageNo survey data has been collected yet
The information was verified by Dr. Arunabha Ray, MD Pharmacology