Neutrexin

Neutrexin is part of the drug class:

• Other agents against amoebiasis and other protozoal diseases

Neutrexin (trimetrexate glucuronate for injection) with concurrent leucovorin administration (leucovorin protection) is indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, trimethoprim-sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is contraindicated.

This indication is based on the results of a randomized, controlled double-blind trial comparing Neutrexin with concurrent leucovorin protection (TMTX/LV) to trimethoprim‑sulfamethoxazole (TMP/SMX) in patients with moderate-to-severe Pneumocystis carinii pneumonia, as well as results of a Treatment IND. These studies are summarized below:

Neutrexin Comparative Study with TMP/SMX

This double-blind, randomized trial initiated by the AIDS Clinical Trials Group (ACTG) in 1988 was designed to compare the safety and efficacy of TMTX/LV to that of TMP/SMX for the treatment of histologically confirmed, moderate-to-severe PCP, defined as (A-a) baseline gradient >30 mmHg, in patients with AIDS.

Of the 220 patients with histologically confirmed PCP, 109 were randomized to receive TMTX/LV and 111 to TMP/SMX. Study patients randomized to TMTX/LV treatment were to receive 45 mg/m2 of TMTX daily for 21 days plus 20 mg/m2 of LV every 6 hours for 24 days. Those randomized to TMP/SMX were to receive 5 mg/kg TMP plus 25 mg/kg SMX four times daily for 21 days.

Response to therapy, defined as alive and off ventilatory support at completion of therapy, with no change in anti-pneumocystis therapy, or addition of supraphysiologic doses of steroids, occurred in fifty percent of patients in each treatment group.

The observed mortality in the TMTX/LV treatment group was approximately twice that in the TMP/SMX treatment group (95% CI: 0.99 - 4.11). Thirty of 109 (27%) patients treated with TMTX/LV and 18 of 111 (16%) patients receiving TMP/SMX died during the 21-day treatment course or 4-week follow-up period. Twenty-seven of 30 deaths in the TMTX/LV arm were attributed to PCP; all 18 deaths in the TMP/SMX arm were attributed to PCP.

A significantly smaller proportion of patients who received TMTX/LV compared to TMP/SMX failed therapy due to toxicity (10% vs. 25%), and a significantly greater proportion of patients failed due to lack of efficacy (40% vs. 24%). Six patients (12%) who responded to TMTX/LV relapsed during the one-month follow-up period; no patient responding to TMP/SMX relapsed during this period. Information is not available as to whether these patients received prophylaxis therapy for PCP.

Treatment IND

The FDA granted a Treatment IND for Neutrexin with leucovorin protection in February 1988 to make Neutrexin therapy available to HIV-infected patients with histologically confirmed PCP who had disease refractory to or who were intolerant of TMP/SMX and/or intravenous pentamidine.

Over 500 physicians in the United States participated in the Treatment IND. Of the first 753 patients enrolled, 577 were evaluable for efficacy. Of these, 227 patients were intolerant of both TMP/SMX and pentamidine (IST - patients intolerant of both standard therapies), 146 were intolerant of one therapy and refractory to the other (RIST - patients refractory to one therapy and intolerant of the other) and 204 were refractory to both therapies (RST - refractory to both standard therapies). This was a very ill patient population; 38% required ventilatory support at entry (Table 1). These studies did not have concurrent control groups. 

The overall survival rate one month after completion of TMTX/LV as salvage therapy was 48%. Patients who had not responded to treatment with both TMP/SMX and pentamidine, of whom 63% required mechanical ventilation at entry, achieved a survival rate of 25% following treatment with TMTX/LV. Survival was 67% in patients who were intolerant to both TMP/SMX and pentamidine (Table 2).

In the Treatment IND, 12% of the patients discontinued Neutrexin therapy (with leucovorin protection) for toxicity.

Neutrexin (trimetrexate glucuronate for injection) is contraindicated in patients with clinically significant sensitivity to trimetrexate, leucovorin, or methotrexate.

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 PRECAUTIONS and DOSAGE AND ADMINISTRATION).

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/m2 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.

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 DOSAGE AND ADMINISTRATION).

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.

Neutrexin (trimetrexate glucuronate for injection) administered without concurrent

leucovorin can cause lethal complications. There has been no extensive experience in humans receiving single intravenous doses of trimetrexate greater than 90 mg/m2/day with concurrent leucovorin. The toxicities seen at this dose were primarily hematologic. In the event of overdose, Neutrexin should be stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6 hours for 3 days. The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2).

Caution: Neutrexin (trimetrexate glucuronate for injection) must be administered with concurrent leucovorin (leucovorin protection) to avoid potentially serious or life-threatening toxicities. Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.

Neutrexin (trimetrexate glucuronate for injection) is administered at a dose of 45 mg/m2 once daily by intravenous infusion over 60 minutes. Leucovorin must be administered daily during treatment with Neutrexin and for 72 hours past the last dose of Neutrexin. Leucovorin may be administered intravenously at a dose of 20 mg/m2 over 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m2, or orally as 4 doses of 20 mg/m2 spaced equally throughout the day. The oral dose should be rounded up to the next higher 25 mg increment. The recommended course of therapy is 21 days of Neutrexin and 24 days of leucovorin.

Neutrexin and leucovorin may alternatively be dosed on a mg/kg basis, depending on the patient’s body weight, using the conversion factors shown in the table below:

Dosage Modifications

Hematologic toxicity: Neutrexin (trimetrexate glucuronate for injection) and leucovorin doses should be modified based on the worst hematologic toxicity according to the following table. If leucovorin is given orally, doses should be rounded up to the next higher 25 mg increment.

Hepatic toxicity: Transient elevations of transaminases and alkaline phosphatase have been observed in patients treated with Neutrexin. Interruption of treatment is advisable if transaminase levels or alkaline phosphatase levels increase to >5 times the upper limit of normal range.

Renal toxicity: Interruption of Neutrexin is advisable if serum creatinine levels increase to > 2.5 mg/dL and the elevation is considered to be secondary to Neutrexin.

Other toxicities: Interruption of treatment is advisable in patients who experience severe mucosal toxicity that interferes with oral intake. Treatment should be discontinued for fever (oral temperature ≥ 105°F/40.5°C) that cannot be controlled with antipyretics.

Leucovorin therapy must extend for 72 hours past the last dose of Neutrexin.

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2. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Medical Journal of Australia 1: 426-428, 1983.
3. Jones RB, et al. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA - A Cancer Journal for Clinicians Sept/Oct, 258-263, 1983.
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Manufactured by:                               Marketed by:

Ben Venue Laboratories, Inc.                  MedImmune Oncology, Inc.

Bedford, OH 44146                                a subsidiary of MedImmune Inc.

                                                             Gaithersburg, MD 20878

Or:                                                        1-877-633-4411

MedImmune Pharma B.V.

6545 CG Nijmegen

The Netherlands

© 2000, MedImmune Oncology, Inc.

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