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Toposar
Overview
What is Toposar?
Toposar (etoposide injection USP) (also commonly known as VP-16) is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. It is 4'-demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-β-D-glucopyranoside]. It is very soluble in methanol and chloroform, slightly soluble in ethanol, and sparingly soluble in water and ether. It is made more miscible with water by means of organic solvents.
Toposar (etoposide injection USP) is available for intravenous use as a sterile 20 mg/mL solution in 100 mg (5 mL), 500 mg (25 mL), or 1 g (50 mL) sterile, multiple dose vials. The pH of the clear, yellow liquid is 3.0 to 4.0.
Each mL contains: 20 mg etoposide, USP, 2 mg citric acid anhydrous, 80 mg polysorbate 80, 650 mg polyethylene glycol 300 (57.5% v/v and 65.0% w/v), and 262 mg dehydrated alcohol (33.2% v/v and 26.2% w/v).
The structural formula is:
CHO M.W. 588.56
What does Toposar look like?
What are the available doses of Toposar?
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What should I talk to my health care provider before I take Toposar?
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How should I use Toposar?
Toposar (etoposide injection) is indicated in the management of the following neoplasms:
Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used with Toposar Injection.
What interacts with Toposar?
Toposar is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.
What are the warnings of Toposar?
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Patients being treated with Toposar must be frequently observed for myelosuppression both during and after therapy. Myelosuppression resulting in death has been reported. Dose-limiting bone marrow suppression is the most significant toxicity associated with Toposar therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of Toposar: platelet count, hemoglobin, white blood cell count, and differential. The occurrence of a platelet count below 50,000/mm or an absolute neutrophil count below 500/mm is an indication to withhold further therapy until the blood counts have sufficiently recovered.
Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. Higher rates of anaphylactic-like reactions have been reported in children who received infusions at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactic-like reactions is uncertain (see section). Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.
For parenteral administration, Toposar should be given only by slow intravenous infusion (usually over a 30- to 60-minute period) since hypotension has been reported as a possible side effect of rapid intravenous injection.
Pregnancy
Toposar can cause fetal harm when administered to a pregnant woman. Etoposide has been shown to be teratogenic in mice and rats.
In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 1/20 of the human dose on a mg/m basis) during organogenesis caused maternal toxicity, embryotoxicity, and teratogenicity (skeletal abnormalities, exencephaly, encephalocele, and anophthalmia); higher doses of 1.2 and 3.6 mg/kg/day (about 1/7 and 1/2 of human dose on a mg/m basis) resulted in 90 and 100% embryonic resorptions. In mice, a single 1 mg/kg (1/16 of human dose on a mg/m basis) dose of etoposide administered intraperitoneally on days 6, 7, or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletal malformations. An I.P. dose of 1.5 mg/kg (about 1/10 of human dose on a mg/m basis) on day 7 of gestation caused an increase in the incidence of intrauterine death and fetal malformations and a significant decrease in the average fetal body weight.
Women of childbearing potential should be advised to avoid becoming pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be warned of the potential hazard to the fetus.
Toposar should be considered a potential carcinogen in humans. The occurrence of acute leukemia with or without a preleukemic phase has been reported in rare instances in patients treated with etoposide alone or in association with other neoplastic agents. The risk of development of a preleukemic or leukemic syndrome is unclear. Carcinogenicity tests with Toposar have not been conducted in laboratory animals.
What are the precautions of Toposar?
General
In all instances where the use of Toposar is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of Toposar therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.
Patients with low serum albumin may be at an increased risk for etoposide associated toxicities.
Drug Interactions
High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone.
Laboratory Tests
Periodic complete blood counts should be done during the course of Toposar treatment. They should be performed prior to each cycle of therapy and at appropriate intervals during and after therapy. At least one determination should be done prior to each dose of Toposar.
Renal Impairment
In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance:
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Data are not available in patients with creatinine clearances <15 mL/min and further dose reduction should be considered in these patients.
| Measured Creatinine Clearance | >50 mL/min | 15 to 50 mL/min |
| etoposide | 100% of dose | 75% of dose |
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Toposar, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Toposar contains polysorbate 80. In premature infants, a life-threatening syndrome consisting of liver and renal failure, pulmonary deterioration, thrombocytopenia, and ascites has been associated with an injectable vitamin E product containing polysorbate 80. Anaphylactic reactions have been reported in pediatric patients (see section).
Geriatric Use
Clinical studies of Toposar for the treatment of refractory testicular tumors did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Of more than 600 patients in four clinical studies in the NDA databases who received Toposar or etoposide phosphate in combination with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC), about one third were older than 65 years. When advanced age was determined to be a prognostic factor for response or survival in these studies, comparisons between treatment groups were performed for the elderly subset. In the one study (etoposide in combination with cyclophosphamide and vincristine compared with cyclophosphamide and vincristine or cyclophosphamide, vincristine, and doxorubicin) where age was a significant prognostic factor for survival, a survival benefit for elderly patients was observed for the etoposide regimen compared with the control regimens. No differences in myelosuppression were seen between elderly and younger patients in these studies except for an increased frequency of WHO Grade III or IV leukopenia among elderly patients in a study of etoposide phosphate or etoposide in combination with cisplatin. Elderly patients in this study also had more anorexia, mucositis, dehydration, somnolence, and elevated BUN levels than younger patients.
In five single-agent studies of etoposide phosphate in patients with a variety of tumor types, 34% of patients were age 65 years or more. WHO Grade III or IV leukopenia, granulocytopenia, and asthenia were more frequent among elderly patients.
Postmarketing experience also suggests that elderly patients may be more sensitive to some of the known adverse effects of etoposide, including myelosuppression, gastrointestinal effects, infectious complications, and alopecia.
Although some minor differences in pharmacokinetic parameters between elderly and nonelderly patients have been observed, these differences were not considered clinically significant.
Etoposide and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see for recommended dosing adjustments in patients with renal impairment).
What are the side effects of Toposar?
The following data on adverse reactions are based on both oral and intravenous administration of Toposar as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.
Hematologic Toxicity
Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after drug administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Fever and infection have also been reported in patients with neutropenia. Death associated with myelosuppression has been reported.
The occurrence of acute leukemia with or without a preleukemic phase has been reported rarely in patients treated with Toposar in association with other antineoplastic agents (see section).
Gastrointestinal Toxicity
Nausea and vomiting are the major gastrointestinal toxicities. The severity of such nausea and vomiting is generally mild to moderate with treatment discontinuation required in 1% of patients. Nausea and vomiting can usually be controlled with standard antiemetic therapy. Mild to severe mucositis/esophagitis may occur. Gastrointestinal toxicities are slightly more frequent after oral administration than after intravenous infusion.
Hypotension
Transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients. It has not been associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has been noted. To prevent this rare occurrence, it is recommended that Toposar be administered by slow intravenous infusion over a 30- to 60-minute period. If hypotension occurs, it usually responds to cessation of the infusion and administration of fluids or other supportive therapy as appropriate. When restarting the infusion, a slower administration rate should be used.
Allergic Reactions
Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving intravenous Toposar and in less than 1% of the patients treated with the oral capsules. These reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as appropriate; however, the reactions can be fatal. Hypertension and/or flushing have also been reported. Blood pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic-like reactions have occurred during the initial infusion of Toposar.
Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain, and/or loss of consciousness have sometimes occurred in association with the above reactions. In addition, an apparent hypersensitivity-associated apnea has been reported rarely.
Rash, urticaria, and/or pruritus have infrequently been reported at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported.
Alopecia
Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66% of patients.
Other Toxicities
The following adverse reactions have been infrequently reported: abdominal pain, aftertaste, constipation, dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness, optic neuritis, interstitial pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associated with allergic reactions), Stevens-Johnson syndrome, and toxic epidermal necrolysis, pigmentation, and a single report of radiation recall dermatitis.
Hepatic toxicity, generally in patients receiving higher doses of the drug than those recommended, has been reported with Toposar. Metabolic acidosis has also been reported in patients receiving higher doses.
Reports of extravasation with swelling have been received postmarketing. Rarely extravasation has been associated with necrosis and venous induration.
The incidences of adverse reactions in the table that follows are derived from multiple data bases from studies in 2,081 patients when Toposar was used either orally or by injection as a single agent.
| Leukopenia (less than 1,000 WBC/mm) | 3 to 17 |
| Leukopenia (less than 4,000 WBC/mm) | 60 to 91 |
| Thrombocytopenia (less than 50,000 platelets/mm) | 1 to 20 |
| Thrombocytopenia (less than 100,000 platelets/mm) | 22 to 41 |
| Anemia | 0 to 33 | Gastrointestinal toxicity |
| Nausea and vomiting | 31 to 43 |
| Abdominal pain | 0 to 2 |
| Anorexia | 10 to 13 |
| Diarrhea | 1 to 13 |
| Stomatitis | 1 to 6 |
| Hepatic | 0 to 3 |
| Alopecia | 8 to 66 |
| Peripheral neurotoxicity | 1 to 2 |
| Hypotension | 1 to 2 |
| Allergic reaction | 1 to 2 |
What should I look out for while using Toposar?
Toposar is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.
Patients being treated with Toposar must be frequently observed for myelosuppression both during and after therapy. Myelosuppression resulting in death has been reported. Dose-limiting bone marrow suppression is the most significant toxicity associated with Toposar therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of Toposar: platelet count, hemoglobin, white blood cell count, and differential. The occurrence of a platelet count below 50,000/mm or an absolute neutrophil count below 500/mm is an indication to withhold further therapy until the blood counts have sufficiently recovered.
Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. Higher rates of anaphylactic-like reactions have been reported in children who received infusions at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactic-like reactions is uncertain (see section). Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.
For parenteral administration, Toposar should be given only by slow intravenous infusion (usually over a 30- to 60-minute period) since hypotension has been reported as a possible side effect of rapid intravenous injection.
What might happen if I take too much Toposar?
No proven antidotes have been established for Toposar overdosage.
How should I store and handle Toposar?
Toposar (etoposide injection USP), 20 mg/mL is supplied as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].DO NOT FREEZE.Toposar (etoposide injection USP), 20 mg/mL is supplied as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].DO NOT FREEZE.Toposar (etoposide injection USP), 20 mg/mL is supplied as follows:Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].DO NOT FREEZE.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Toposar has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the G portion of the cell cycle in mammalian cells. Two different dose-dependent responses are seen. At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 mcg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA topoisomerase II or the formation of free radicals.
Non-Clinical Toxicology
Toposar is contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation.Patients being treated with Toposar must be frequently observed for myelosuppression both during and after therapy. Myelosuppression resulting in death has been reported. Dose-limiting bone marrow suppression is the most significant toxicity associated with Toposar therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent cycle of Toposar: platelet count, hemoglobin, white blood cell count, and differential. The occurrence of a platelet count below 50,000/mm or an absolute neutrophil count below 500/mm is an indication to withhold further therapy until the blood counts have sufficiently recovered.
Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension. Higher rates of anaphylactic-like reactions have been reported in children who received infusions at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactic-like reactions is uncertain (see section). Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.
For parenteral administration, Toposar should be given only by slow intravenous infusion (usually over a 30- to 60-minute period) since hypotension has been reported as a possible side effect of rapid intravenous injection.
High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in total body clearance of etoposide compared to etoposide alone.
In all instances where the use of Toposar is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of Toposar therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.
Patients with low serum albumin may be at an increased risk for etoposide associated toxicities.
The following data on adverse reactions are based on both oral and intravenous administration of Toposar as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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