Peri-infusional adverse reactions to rituximab in patients with non-Hodgkin's lymphoma.

BACKGROUND AND AIMS: Rituximab is effective in the treatment of B-cell lymphoid malignances and some autoimmune diseases. Most patients receiving the first infusion of rituximab experience symptoms that decrease with subsequent infusions. It is assumed that the first dose of rituximab should be infused slowly during a 6-h period and during 4-h periods subsequently. The aim of the study was to evaluate the frequency and severity of adverse reactions to rituximab in patients with non-Hodgkin's lymphoma. METHODS: This was an intensive pharmacovigilance prospective, observational, open labeled, multicenter cohort study conducted in 12 hospitals. Adults requiring treatment with rituximab (375 mg/m(2) body surface area) alone or with chemotherapy were included. Adverse reactions were graded according to the National Cancer Institute scale, whereas causality was established using the Naranjo algorithm. Infusions were classified as fast (0-90 min) and slow (>91 min). Fast infusions were used to analyze the associated adverse reactions. RESULTS: We included 550 adult patients. Total infusion episodes were 1,749 and 52 adverse reactions were reported in 22 patients (4%). Thirty-one of 52 adverse reactions occurred during the first infusion. The risk of adverse reactions was lower with the fast infusions (10/52 adverse reactions [19.23%]). All adverse effects were mild. Twenty-three adverse effects were possibly related to rituximab. CONCLUSIONS: Rituximab can be infused at a fast rate without an increase in adverse reactions. Peri-infusional adverse reactions are similar to those described for other populations but the incidence rate is lower. Rituximab has a favorable safety profile in patients with non-Hodgkin's lymphoma.

Additive, but not synergistic antinociceptive effect of codeine and indomethacin combinations in the formalin test in the rat.

Combinations of NSAIDs and opioids are currently employed for the treatment of moderate-to-severe pain in order to obtain an increased analgesic esponse, allowing the use of low doses of each agent, hence limiting side effects. There is active interest in developing combinations for oral adminstration. Therefore, we examined the antinociceptive activity of oral indomethacin and codeine, alone and incombination, in the formalin test in the rat. Both codeine and indomethacin, when given alone, produced a dose-dependent antinociceptive effect. ED30 values were 5.0 +/- 0.31 and 54.8 +/- 5.8 mg/kg for codeine and indomethacin respectively. Codeine-indomethacin combinations also produced a dose-dependent antinociceptive effect. The interaction between these two agents was characterized by isobolographic analysis using a fixed-ratio dosing strategy. Accordingly, the theoretical ED30 of the combination for a pure additive interaction, (i.e., that the combined effect is the result of the sum of the effects of the individual components), was 29.9 +/- 2.9 mg/kg. The observed ED30 for the codeine-indomethacin combination was 21.7 +/- 2.34 mg/kg. Comparison by the Student "t" test showed that there is no statistically significant difference (p > 0.05) between the observed and the theoretical DE30 values and thus a synergistic interaction is ruled out. We conclude that the indomethacin-codeine interaction is additive and does not result in analgesic synergism, unlike other combinations such as codeine-diclofenac. Our results show that, since not all the opioid-NSAID associations result in synergism, the individual components of a combination should be carefully selected, and that mechanisms of synergy may suggest actions of the NSAID partner not previously known.