INDICATIONS AND USAGE
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 trimethoprimsulfamethoxazole (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.TABLE 1 TREATMENT IND Baseline Characteristics
IST(n = 227)RIST(n = 146)RST(n = 204)TOTAL(n = 577)
Ventilatory Support Required
n (%)39(17)50(34)129(63)218(38)
Median Days on Standard Therapy10121614
First Episode of PCPn (%)104(46)103(71)190(93)397(69)
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
Therapy
ISTRISTRST
All Patients153/227(67%)73/146(50%)50/204(25%)
Baseline Ventilatory Support9/39(23%)15/50(30%)18/129(14%)
No Baseline Ventilatory Support144/188(77%)58/96(60%)32/75(43%)
In the Treatment IND, 12% of the patients discontinued Neutrexin therapy (with leucovorin protection) for toxicity.