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Neutrexin
Overview
What is Neutrexin?
What does Neutrexin look like?
What are the available doses of Neutrexin?
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What should I talk to my health care provider before I take Neutrexin?
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How should I use Neutrexin?
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What interacts with Neutrexin?
Neutrexin (trimetrexate glucuronate for injection) is contraindicated in patients with clinically significant sensitivity to trimetrexate, leucovorin, or methotrexate.
What are the warnings of Neutrexin?
When
thallium myocardial perfusion imaging is performed with intravenous dipyridamole,
parenteral aminophylline should be readily available for relieving adverse
events such as bronchospasm or chest pain. Vital signs should be monitored
during, and for 10 to 15 minutes following, the intravenous infusion of dipyridamole
and an electrocardiographic tracing should be obtained using at least one
chest lead. Should severe chest pain or bronchospasm occur, parenteral aminophylline
may be administered by slow intravenous injection (50 to 100 mg over 30 to
60 seconds) in doses ranging from 50 to 250 mg. In the case of severe
hypotension, the patient should be placed in a supine position with the head
tilted down if necessary, before administration of parenteral aminophylline.
If 250 mg of aminophylline does not relieve chest pain symptoms within a few
minutes, sublingual nitroglycerin may be administered. If chest pain continues
despite use of aminophylline and nitroglycerin, the possibility of myocardial
infarction should be considered. If the clinical condition of a patient with
an adverse event permits a one minute delay in the administration of parenteral
aminophylline, thallium-201 may be injected and allowed to circulate for one
minute before the injection of aminophylline. This will allow initial thallium
perfusion imaging to be performed before reversal of the pharmacologic effects
of dipyridamole on the coronary circulation.
Neutrexin (trimetrexate glucuronate for injection) must be used with concurrent leucovorin to avoid potentially serious or life-threatening complications including bone marrow suppression, oral and gastrointestinal mucosal ulceration, and renal and hepatic dysfunction. Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin. Patients should be informed that failure to take the recommended dose and duration of leucovorin can lead to fatal toxicity. Patients should be closely monitored for the development of serious hematologic adverse reactions (see and ).
Neutrexin can cause fetal harm when administered to a pregnant woman. Trimetrexate has been shown to be fetotoxic and teratogenic in rats and rabbits. Rats administered 1.5 and 2.5 mg/kg/day intravenously on gestational days 6-15 showed substantial postimplantation loss and severe inhibition of maternal weight gain. Trimetrexate administered intravenously to rats at 0.5 and 1.0 mg/kg/day on gestational days 6-15 retarded normal fetal development and was teratogenic. Rabbits administered trimetrexate intravenously at daily doses of 2.5 and 5.0 mg/kg/day on gestational days 6-18 resulted in significant maternal and fetal toxicity. In rabbits, trimetrexate at 0.1 mg/kg/day was teratogenic in the absence of significant maternal toxicity. These effects were observed using doses 1/20 to 1/2 the equivalent human therapeutic dose based on a mg/m basis. Teratogenic effects included skeletal, visceral, ocular, and cardiovascular abnormalities. If Neutrexin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
What are the precautions of Neutrexin?
General
Patients receiving Neutrexin (trimetrexate glucuronate for injection) may experience severe hematologic, hepatic, renal, and gastrointestinal toxicities. Caution should be used in treating patients with impaired hematologic, renal, or hepatic function. Patients who require concomitant therapy with nephrotoxic, myelosuppressive, or hepatotoxic drugs should be treated with Neutrexin at the discretion of the physician and monitored carefully. To allow for full therapeutic doses of Neutrexin, treatment with zidovudine should be discontinued during Neutrexin therapy.
Neutrexin-associated myelosuppression, stomatitis, and gastrointestinal toxicities generally can be ameliorated by adjusting the dose of leucovorin. Mild elevations in transaminases and alkaline phosphatase have been observed with Neutrexin administration and are usually not cause for modification of Neutrexin therapy (see ). Seizures have been reported rarely (< 1%) in AIDS patients receiving Neutrexin; however, a causal relationship has not been established. Trimetrexate is a known inhibitor of histamine metabolism. Hypersensitivity/allergic type reactions including but not limited to rash, chills/rigors, fever, diaphoresis and dypsnea have occurred with trimetrexate primarily when it is administered as a bolus infusion or at doses higher than those recommended for PCP, and most frequently in combination with 5FU and leucovorin. In rare cases, anaphylactoid reactions, including acute hypotension and loss of consciousness have occurred. Neutrexin infusion should be permanently discontinued in all patients with severe hypersensitivity reactions. Epinephrine should be available for treatment of acute allergic symptoms.
Neutrexin has not been evaluated clinically for the treatment of concurrent pulmonary conditions such as bacterial, viral, or fungal pneumonia or mycobacterial diseases. activity has been observed against , complex, gram positive cocci, and gram negative rods. If clinical deterioration is observed in patients, they should be carefully evaluated for other possible causes of pulmonary disease and treated with additional agents as appropriate.
Laboratory Tests
Patients receiving Neutrexin with leucovorin protection should be seen frequently by a physician. Blood tests to assess the following parameters should be performed at least twice a week during therapy: hematology (absolute neutrophil counts [ANC], platelets), renal function (serum creatinine, BUN), and hepatic function (AST, ALT, alkaline phosphatase).
Drug Interactions
Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term studies in animals to evaluate the carcinogenic potential of trimetrexate have not been performed.
Trimetrexate was not mutagenic when tested using the standard Ames mutagenicity assay with and without metabolic activation. Trimetrexate did not induce mutations in Chinese hamster lung cells or sister-chromatid exchange in Chinese hamster ovary cells. Trimetrexate did induce an increase in the chromosomal aberration frequency of cultured Chinese hamster lung cells; however, trimetrexate showed no clastogenic activity in a mouse micronucleus assay.
No studies have been conducted to evaluate the potential of trimetrexate to impair fertility. However, during standard toxicity studies conducted in mice and rats, degeneration of the testes and spermatocytes including the arrest of spermatogenesis was observed.
Pregnancy
See .
Pregnancy Category D
Nursing Mothers
It is not known if trimetrexate 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 trimetrexate, it is recommended that breast feeding be discontinued if the mother is treated with Neutrexin.
Pediatric Use
The safety and effectiveness of Neutrexin for the treatment of histologically confirmed PCP has not been established for patients under 18 years of age. Two children, ages 15 months and 9 months, were treated with trimetrexate and leucovorin using a dose of 45 mg/m of trimetrexate per day for 21 days and 20 mg/m of leucovorin every 6 hours for 24 days. There were no serious or unexpected adverse effects.
What are the side effects of Neutrexin?
Because many patients who participated in clinical trials of Neutrexin (trimetrexate glucuronate for injection) had complications of advanced HIV disease, it is difficult to distinguish adverse events caused by Neutrexin from those resulting from underlying medical conditions.
Table 3 lists the adverse events that occurred in ≥ 1% of the patients who participated in the Comparative Study of Neutrexin plus leucovorin versus TMP/SMX.
Laboratory toxicities were generally manageable with dose modification of
trimetrexate/leucovorin (see ).
Table 4 lists the adverse events resulting in discontinuation of study therapy in the Neutrexin Comparative Study with TMP/SMX. Twenty-nine percent of the patients on the TMP/SMX arm discontinued therapy due to adverse events compared to 10% of the patients treated with TMTX/LV (p < 0.001).
Hematologic toxicity was the principal dose-limiting side effect.
| Adverse Events | Number and Percent (%) of Patients with Adverse Events | |||
| TMTX/LV | (n = 109) | TMP/SMX | (n = 111) | |
| Non-Laboratory Adverse Events: | ||||
| Fever | 9 | (8.3) | 14 | (12.6) |
| Rash/Pruritus | 6 | (5.5) | 14 | (12.6) |
| Nausea/Vomiting | 5 | (4.6) | 15 | (13.5) |
| Confusion | 3 | (2.8) | 3 | (2.7) |
| Fatigue | 2 | (1.8) | 0 | (0.0) |
| Hematologic Toxicity: | ||||
| Thrombocytopenia (75,000/mm) | 33 | (30.3) | 37 | (33.3) |
| Anemia (Hgb <8 g/dL) | 11 | (10.1) | 17 | (15.3) |
| Neutropenia (1000/mm) | 8 | (7.3) | 10 | (9.0) |
| Hepatotoxicity: | ||||
| Increased AST (>5 x ULN) | 15 | (13.8) | 10 | (9.0) |
| Increased ALT (>5 x ULN) | 12 | (11.0) | 13 | (11.7) |
| Increased Alkaline Phosphatase (>5 x ULN) | 5 | (4.6) | 3 | (2.7) |
| Increased Bilirubin (2.5 x ULN) | 2 | (1.8) | 1 | (0.9) |
| Renal: | ||||
| Increased Serum Creatinine (>3 x ULN) | 1 | (0.9) | 2 | (1.8) |
| Electrolyte Imbalance: | ||||
| Hyponatremia | 5 | (4.6) | 10 | (9.0) |
| Hypocalcemia | 2 | (1.8) | 0 | (0.0) |
| No. of Patients With at Least one Adverse Event | 58 | (53.2) | 60 | (54.1) |
| Adverse Events | Number and Percent (%) of Patients Discontinued for Adverse Events | |||
| TMTX/LV | (n = 109) | TMP/SMX | (n = 111) | |
| Non-Laboratory Adverse Events: | ||||
| Rash/Pruritus | 3 | (2.8) | 5 | (4.5) |
| Fever | 2 | (1.8) | 4 | (3.6) |
| Nausea/Vomiting | 1 | (0.9) | 8 | (7.2) |
| Neurologic Toxicity | 1 | (0.9) | 2 | (1.8) |
| Hematologic Toxicity: | ||||
| Neutropenia (1000/mm) | 4 | (3.7) | 6 | (5.4) |
| Thrombocytopenia (75,000/mm) | 0 | (0.0) | 4 | (3.6) |
| Anemia (Hgb <8 g/dL) | 0 | (0.0) | 4 | (3.6) |
| Hepatotoxicity: | ||||
| Increased AST (>5 x ULN) | 3 | (2.8) | 9 | (8.1) |
| Increased ALT (>5 x ULN) | 1 | (0.9) | 4 | (3.6) |
| Increased Alkaline Phosphatase (>5 x ULN) | 0 | (0.0) | 1 | (0.9) |
| Electrolyte Imbalance: | ||||
| Hyponatremia | 0 | (0.0) | 3 | (2.7) |
| No. of Patients Discontinuing Therapy Due to an Adverse Event | 11 | (10.1) | 32 | (28.8) |
What should I look out for while using Neutrexin?
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What might happen if I take too much Neutrexin?
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How should I store and handle Neutrexin?
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