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 (trimetrexate glucuronate inj) 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 (trimetrexate glucuronate inj) 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 (trimetrexate glucuronate inj) with leucovorin protection in February 1988 to make Neutrexin (trimetrexate glucuronate inj) 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.

TABLE 1: TREATMENT IND Baseline Characteristics

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).

TABLE 2: TREATMENT IND Survival Rate One Month After Completion of Neutrexin (trimetrexate glucuronate inj) Therapy

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

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 (trimetrexate glucuronate inj) and for 72 hours past the last dose of Neutrexin (trimetrexate glucuronate inj) . 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 (trimetrexate glucuronate inj) and 24 days of leucovorin.

Neutrexin (trimetrexate glucuronate inj) 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.

TABLE 5: DOSE MODIFICATIONS FOR HEMATOLOGIC TOXICITY

Hepatic toxicity: Transient elevations of transaminases and alkaline phosphatase have been observed in patients treated with Neutrexin (trimetrexate glucuronate inj) . 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 (trimetrexate glucuronate inj) is advisable if serum creatinine levels increase to > 2.5 mg/dL and the elevation is considered to be secondary to Neutrexin (trimetrexate glucuronate inj) .

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 (trimetrexate glucuronate inj) .

Reconstitution And Dilution

Each vial of Neutrexin (trimetrexate glucuronate for injection) should be reconstituted in accordance with labeled instructions with either 5% Dextrose Injection, USP, or Sterile Water for Injection, USP, to yield a concentration of 12.5 mg of trimetrexate per mL (complete dissolution should occur within 30 seconds). The reconstituted product will appear as a pale greenish-yellow solution and must be inspected visually prior to dilution. Do not use if cloudiness or precipitate is observed. Neutrexin (trimetrexate glucuronate inj) should not be reconstituted with solutions containing either chloride ion or leucovorin, since precipitation occurs instantly.

After reconstitution, the solution should be used immediately; however, the solution is stable for 6 hours at room temperature (20 to 25ºC), or 24 hours under refrigeration (2-8°C).

Prior to administration, the reconstituted solution should be further diluted with 5% Dextrose Injection, USP, to yield a final concentration of 0.25 to 2 mg of trimetrexate per mL. The diluted solution should be administered by intravenous infusion over 60 minutes. Neutrexin (trimetrexate glucuronate inj) should not be mixed with solutions containing either chloride ion or leucovorin, since precipitation occurs instantly. The diluted solution is stable under refrigeration or at room temperature for up to 24 hours. Do not freeze. Discard any unused portion after 24 hours. The intravenous line must be flushed thoroughly with at least 10 mL of 5% Dextrose Injection, USP, before and after administering Neutrexin (trimetrexate glucuronate inj) .

Leucovorin protection may be administered prior to or following Neutrexin (trimetrexate glucuronate inj) . In either case, the intravenous line must be flushed thoroughly with at least 10 mL of 5% Dextrose Injection, USP. Leucovorin calcium for injection should be diluted according to the instructions in the leucovorin package insert, and administered over 5 to 10 minutes every 6 hours.

Caution: Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Neutrexin (trimetrexate glucuronate inj) forms a precipitate instantly upon contact with chloride ion or leucovorin, therefore it should not be added to solutions containing sodium chloride or other anions. Neutrexin (trimetrexate glucuronate inj) and leucovorin solutions must be administered separately. Intravenous lines should be flushed with at least 10 mL of 5% Dextrose Injection, USP, between Neutrexin (trimetrexate glucuronate inj) and leucovorin infusions.

Handling And Disposal

If Neutrexin (trimetrexate glucuronate for injection) contacts the skin or mucosa, immediately wash thoroughly with soap and water. Procedures for proper disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published ^(1-5).

Neutrexin (trimetrexate glucuronate for injection) is supplied as a sterile lyophilized powder in either 5 mL or 30 mL vials. Each 5 mL vial contains trimetrexate glucuronate equivalent to 25 mg of trimetrexate. Each 30 mL vial contains trimetrexate glucuronate equivalent to 200 mg of trimetrexate.

The 5 mL vials are packaged and available in two market presentations as listed below:

10 Pack - 10 vials in a white chip-board carton (NDC 58178-020-10)
50 Pack - 2 trays of 25 vials per shrink-wrapped tray (NDC 58178-020-50)

The 30 mL vials are packaged and available as listed below:

Single Pack - 1 vial (NDC 58178-021-01)

Store at controlled room temperature 20° to 25°C (68° to 77°F). Protect from exposure to light.

REFERENCES

1. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. Journal of the American Medical Association March 15, 1985.

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.

4. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic Drugs in Hospitals. American Journal of Hospital Pharmacy 42: 131-137, 1985.

5. OSHA Work Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. American Journal of Hospital Pharmacy 43: 1193-1204, 1986.

Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146. Or: MedImmune Pharma B.V. 6545 CG Nijmegen, The Netherlands. Marketed by: MedImmune Oncology, Inc. a subsidiary of MedImmune Inc. Gaithersburg, MD 20878. 1-877-633-4411. Revision Date 1/2005.

Last reviewed on RxList: 4/20/2009
This monograph has been modified to include the generic and brand name in many instances.