April 26, 2017
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Discontinued Warning IconPlease Note: This Brand Name drug is no longer available in the US.
(Generic versions may still be available.)

Side Effects


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 (trimetrexate glucuronate inj) 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 (trimetrexate glucuronate inj) plus leucovorin versus TMP/SMX.

TABLE 3: NEUTREXIN (trimetrexate glucuronate inj) COMPARATIVE TRIAL Comparison of Adverse Events Reported for ≥ 1% of Patients

Adverse Events Number and Percent (%) of Patients with Adverse Events
(n = 109)
(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)a 15 (13.5)a
  Confusion 3 (2.8) 3 (2.7)
  Fatigue 2 (1.8) 0 (0.0)
Hematologic Toxicity:
  Neutropenia ( ≤ 1000/mm3) 33 (30.3) 37 (33.3)
  Thrombocytopenia ( ≤ 75,000/mm3) 11 (10.1) 17 (15.3)
  Anemia (Hgb < 8 g/dL) 8 (7.3) 10 (9.0)
  Increased AST ( > 5 x ULNb) 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)
  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 Eventc 58 (53.2) 60 (54.1)
a Statistically significant difference between treatment groups (Chi-square: p=0.022)
b ULN = Upper limit of normal range
c Patients could have reported more than one adverse event; therefore, the sum of adverse events exceeds the number of patients

Laboratory toxicities were generally manageable with dose modification of trimetrexate/leucovorin (see DOSAGE AND ADMINISTRATION).

Table 4 lists the adverse events resulting in discontinuation of study therapy in the Neutrexin (trimetrexate glucuronate inj) 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).

TABLE 4: NEUTREXIN (trimetrexate glucuronate inj) COMPARATIVE TRIAL Adverse Events Resulting in Discontinuation of Therapy

Adverse Events Number and Percent (%) of Patients Discontinued for Adverse Eventsb
(n = 109)
(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)c 2 (1.8)
Hematologic Toxicity:
  Neutropenia ( ≤ 1000/mm3) 4 (3.7) 6 (5.4)
  Thrombocytopenia ( ≤ 75,000/mm3) 0 (0.0) 4 (3.6)
  Anemia (Hgb < 8 g/dL) 0 (0.0) 4 (3.6)
  Increased AST ( > 5 x ULNa) 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 Eventb 11 (10.1)d 32 (28.8)d
a ULN = Upper limit of normal range
b Patients could discontinue therapy due to more than one toxicity; therefore the sum exceeds number of patients who discontinued due to toxicity
c Patient discontinued TMTX/LV due to seizure, though causal relationship could not be established.
d Statistically significant difference between treatment groups (Chi-square: p < 0.001)

Hematologic toxicity was the principal dose-limiting side effect.

Read the Neutrexin (trimetrexate glucuronate inj) Side Effects Center for a complete guide to possible side effects


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. In vitro 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 in vitro 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.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 1/11/2017

Side Effects

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