Rechallenge In Patients Research Articles

Weekly docetaxel rechallenge in patients with hormone-resistant prostate cancer refractory to conventionally three weekly docetaxel.

e15004 Background: The common standard treatment for hormone resistant prostate cancer is a 3-weekly (q3w) schedule with prednisone 10 mg qd and docetaxel 75 mg/m2 q3w. In case of progression almost 2/3 of patients profit from a docetaxel rechallenge. If the PSA rises again therapy is usually discontinued. Methods: We identified 31 out of 106 patients retrospectively (Jun 2004-Oct 2009) who were reportedly refractory to the q3w schedule and were continued on a weekly (q1w) schedule of prednisone 10 mg qd and docetaxel 30 mg/m2 q1w. 5 patients never responded to q3w, 25 patients responded initially to q3w but then became progressive, 1 patient showed a PSA decline to q3w but was regarded as clinically progressive. Median time to PSA nadir under q3w schedule was 12 weeks. Average age was 71 years and median q3w treatment of docetaxel was 16 weeks. Median baseline PSA was 96 ng/ml. Under the q3w schedule median PSA decline was about 43%. Results: Surprisingly 80% (25/31) of the q3w pretreated patients showed a remarkable median PSA decline of 46% to q1w treatment. Only 6 patients showed PSA progression. Median treatment duration of q1w was 16 weeks. Median time to PSA nadir was 13 weeks and median PSA at the time of rechallenge was 112 ng/ml. PSA response greater than 50% was reached in 45% (14) of patients in the q3w schedule and in 39% (12) of patients in the q1w schedule. Dose intensity of both schedules was comparable (q3w: 28mg/m2, q1w: 27mg/m2). Toxicity profile changed slightly (more nail problems and PNP in q1w) but the q1w schedule was generally well tolerated. Median overall treatment duration was 16 weeks for both schedules. Conclusions: This retrospectively analysed data should be controlled prospectively but until further data is available we suggest a rechallenge with a q1w schedule of docetaxel in all patients refractory to a q3w schedule before discontinuing the drug, notably also for primary nonresponder to the q3w schedule. No significant financial relationships to disclose.

Add-On Filgrastim During Clozapine Rechallenge in Patients With a History of Clozapine-Related Granulocytopenia/Agranulocytosis

Back to table of contents Previous article Next article Letters to the EditorFull AccessAdd-On Filgrastim During Clozapine Rechallenge in Patients With a History of Clozapine-Related Granulocytopenia/AgranulocytosisGRIGORI JOFFE M.D., Ph.D.,SAANA ESKELINEN M.D.EILA SAILAS M.D.,GRIGORI JOFFE M.D., Ph.D.Search for more papers by this author,SAANA ESKELINEN M.D.Search for more papers by this authorEILA SAILAS M.D.Search for more papers by this author,Published Online:1 Feb 2009https://doi.org/10.1176/appi.ajp.2008.08081295AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Clozapine treatment is often discontinued as a result of clozapine-related granulocytopenia/agranulocytosis, even among patients who are resistant to other antipsychotics. Moreover, clozapine re-exposure is sometimes undertaken among patients with a history of clozapine-related granulocytopenia/agranulocytosis whose previous good response to the drug cannot be maintained with other treatments. Prior to a recent report of the failure to prevent clozapine-related granulocytopenia/agranulocytosis with concomitant granulocyte colony stimulating factor filgrastim (1) , we used a clozapine-filgrastim combination to treat five patients with a history of clozapine-related granulocytopenia/agranulocytosis. Our attempts were encouraged by several earlier successful case reports (2) . We examined five schizophrenia patients who were resistant to numerous antipsychotic drugs (demographic and clinical characteristics of these patients are presented in a supplemental table that accompanies the online version of this letter). During previous clozapine exposure, these patients achieved a clinical response rating (physician’s global impression based on patient records) of at least “fair.” In all cases, treatment with clozapine had to be discontinued as a result of clozapine-related granulocytopenia/agranulocytosis. One patient (patient 2) also developed sepsis, which was successfully treated.Despite usual treatment, severe and prolonged psychotic states re-emerged in the patients. Consequently, a clinical decision for the use of clozapine rechallenge with concomitant filgrastim was made following a thorough risk-benefit consideration. After complete description of the possible risks was given, oral informed consent was obtained from each patient. In four patients, clozapine (step-wise increase) and filgrastim (dosage was according to clinical judgment, with no standard schedule applied) were started simultaneously, and in one patient, filgrastim was added to clozapine 2 weeks after reonset of clozapine-related granulocytopenia/agranulocytosis.For each patient, a clinical response of at least “fair” was reachieved. However, four patients redeveloped clozapine-related granulocytopenia/agranulocytosis. Among these, clozapine treatment was discontinued for two patients whose granulocyte count dropped below the critical <1xE/l level. At the time of the present report, clozapine treatment was continued for the three remaining patients, despite the reoccurrence of noncritical clozapine-related granulocytopenia/agranulocytosis in two of these patients.The patient (who had sepsis at first clozapine exposure) whose clozapine treatment was discontinued developed full-blown agranulocytosis, with peritonsillitis, epiglottitis, and sepsis. The condition was resolved later, with no sequelae.As a result of our small data size, we were unable to identify a clear-cut relationship between filgrastim dosing and a clozapine-related granulocytopenia/ agranulocytosis protecting effect. However, both patients who received a filgrastim dose of >0.3 mg/week were able to continue clozapine treatment, despite re-emergence of clozapine-related granulocytopenia/agranulocytosis, and one patient who received a dose of 0.3 mg/week developed agranulocytosis and sepsis.It has been previously suggested that severe clozapine-induced agranulocytosis is caused by an immunoallergic idiosyncratic mechanism that is unrelated to a granulocyte colony stimulating factor, while mild granulocytopenia results from prolonged clozapine exposure and decreased granulocyte production by hypoplastic bone marrow.We feel that, despite an add-on filgrastim, clozapine rechallenge is potentially dangerous, at least for patients who have a history of severe clozapine-related agranulocytosis and sepsis. In the future, if clinicians decide to use the clozapine-filgrastim combination, it is important that they seek to publish their cases, since a greater number of cases in the literature may enable the detection of plausible risk factors.Helsinki, FinlandKellokoski, FinlandThe authors report no competing interests.This letter (doi: 10.1176/appi.ajp.2008.08081295) was accepted for publication in November 2008.

Testing the Hypothesis that Selenium Deficiency is a Risk Factor for Clozapine-Induced Agranulocytosis in Rats

Clozapine is an effective atypical antipsychotic associated with a relatively high incidence of drug-induced agranulocytosis. It forms a reactive nitrenium ion metabolite upon oxidation by peripheral neutrophils and their precursors in the bone marrow. Although the mechanism of this idiosyncratic drug reaction is still unknown, the observation that it does not occur rapidly on rechallenge of patients with a history of clozapine-induced agranulocytosis suggests that it is not immune-mediated. Previous studies by other research groups had found that patients on clozapine had lower plasma and red blood cell levels of selenium. The reactive metabolite of clozapine reacts with glutathione, and therefore, it is likely that it also binds to selenocysteine-containing proteins, such as glutathione peroxidase, thioredoxin reductase, and protein disulfide isomerase. We set out to test the hypothesis that clozapine-induced agranulocytosis is associated with selenium deficiency with rats on a selenium-deficient diet. We studied the effects of clozapine on selenium levels and the effect of selenium deficiency on leukocyte and neutrophil counts and clozapine covalent binding. We did not observe any significant difference between clozapine-treated rats given a selenium-adequate or deficient diet. Therefore, it is unlikely that selenium deficiency is a major risk factor for clozapine-induced agranulocytosis.

Pharmacists Investigating Adverse Penicillin Responses—Pilot Study

ABSTRACTBackgroundPenicillins are used first‐line for many infections and are commonly associated with adverse drug responses. Pharmacists can take a detailed adverse drug response history and provide such information to prescribers.AimTo investigate and quantify the nature of adverse penicillin responses of hospital inpatients and to develop a tool to enable pharmacists to provide recommendations on potential rechallenge of patients with a history of adverse response to penicillin.MethodPatients were administered a structured interview to classify the true nature of their documented adverse penicillin responses. A literature review was undertaken to develop a flowchart to enable pharmacists to advise on penicillin rechallenge in patients with a history of adverse response to penicillin.Results84 patients were identified and 49 (58%) met the inclusion criteria. Of these 18% had either a true penicillin allergy or were not able to recall the nature of their reaction. Of the 49 patients interviewed, 82% could be rechallenged with a penicillin. The literature review identified publications that allowed the development of a flowchart to assist pharmacists in evaluating reactions and recommending future therapy for these patients.ConclusionIn this small cohort, a significant proportion of patients were considered appropriate for rechallenge with penicillins. Knowledge of the sequelae of previous exposure to penicillins can inform decisions should a penicillin be indicated for treatment. The flowchart will allow pharmacists to make recommendations to the patient's medical team.

Cotrimoxazole for prophylaxis or treatment of opportunistic infections of HIV/AIDS in patients with previous history of hypersensitivity to cotrimoxazole

Opportunistic infections continue to cause a significant amount of morbidity and mortality worldwide in patients infected with HIV. Trimethoprim-sulfamethoxazole (cotrimoxazole) is used in the treatment and prophylaxis of several opportunistic infections. In patients with HIV/AIDS, cotrimoxazole use can cause a higher rate of adverse drug reactions than in the general population. Given the cost-effectiveness of cotrimoxazole, the management of these adverse reactions has included continuing the drug (treating-through) and reintroducing the drug at a later date, either using dose-escalation (desensitization), or rechallenge at full dose. This systematic review is the first to examine the differences in patient outcomes between these strategies. To compare the rate of discontinuation of cotrimoxazole and adverse reactions among the three strategies of treating-through, desensitization, and rechallenge in patients living with HIV who previously had an adverse reaction to cotrimoxazole. We searched MEDLINE, EMBASE, LILACS, The Cochrane Library, Meeting Abstracts, AIDSTRIALS, ACTIS, Current Controlled Trials, The National Institutes of Health Clinical Trials Registry, and CenterWatch (search date May 2006). Randomised trials comparing treating-through, rechallenge, or desensitization of cotrimoxazole treatment or prophylaxis in adults (age 18 years or over) and/or children (age 17 years or under). Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear, a third reviewer resolved conflicts and/or trial authors were contacted for further details. Three trials that examined cotrimoxazole prophylaxis and involving 268 adults were included. Meta-analysis of these studies found a beneficial effect of using a desensitization protocol over a rechallenge protocol at six months of follow-up for preventing discontinuation of cotrimoxazole (number needed to treat (NNT) 7.14, 95% confidence interval (CI) 4.0-33.0), and for lower incidence of overall hypersensitivity (NNT 4.55, 95% CI 3.03-9.09). No severe hypersensitivity reactions occurred for either protocol in the three studies. In the small trials included in this review, when compared to cotrimoxazole rechallenge for prophylaxis of opportunistic infections, cotrimoxazole desensitization resulted in fewer treatment discontinuations and overall adverse reactions in HIV-infected patients with a previous history of mild or moderate hypersensitivity to cotrimoxazole. Paediatric data and trials in resource-poor settings are urgently required. Further randomised controlled trials are also needed for the treatment of opportunistic infections, treating-through, adjunctive medications, and different desensitization-dosing schedules.

Outcomes in 45 Patients With Statin-Associated Myopathy

Published studies regarding statin-associated myopathy may describe more dramatic patient presentations, potentially leading to inaccurate characterization of the condition. Furthermore, long-term outcomes and responses to statin rechallenge in patients with statin-associated myopathy are largely unknown. The University of Wisconsin Hospital and Clinics Medical Informatics Department identified 437 patients with International Classification of Diseases, Ninth Revision codes potentially representing cases of statin-associated myopathy from more than 13 years of inpatient and outpatient data; 45 of these individuals were diagnosed as having statin-associated myopathy. Using a standardized form, 2 researchers abstracted all the case records to define the clinical course of statin-induced myopathy. The mean (SD) duration of statin therapy before symptom onset was 6.3 (9.8) months. Resolution of muscle pain occurred a mean (SD) of 2.3 (3.0) months after discontinuation of statin therapy. Six patients (13%) were hospitalized for the management of rhabdomyolysis; 2 had reversible renal dysfunction, and 1 with preexisting renal insufficiency subsequently began lifelong dialysis. Hospitalized patients developed myopathy more quickly after initiating statin therapy (1.3 vs 7.1 months; P = .048) and were more likely to be taking concomitant medications known to increase the risk of statin-associated myopathy (P = .03). Thirty-seven patients received another statin after an episode of statin-associated myopathy; 21 (57%) reported recurrent muscle pain, whereas 16 (43%) tolerated other statins without recurrent symptoms. Patients with statin-associated myopathy experienced full resolution of muscle pain on cessation of statin therapy. Although no deaths occurred, 13% of the patients required hospitalization for rhabdomyolysis. Recurrent muscle pain was common on statin rechallenge.

Cross-sensitivity between paclitaxel and docetaxel in a women's cancers program

Purpose. With the use of steroid premedication, the incidence of severe hypersensitivity reactions (S-HSR) to paclitaxel is estimated to be 2%. For those who develop a S-HSR to paclitaxel, docetaxel has been employed as an alternative agent though the presence of cross-sensitivity has not been established. We sought to define the incidence of S-HSR to docetaxel following a paclitaxel S-HSR in an academic women's cancer program. Methods. Patients treated with either paclitaxel (P) or docetaxel (D) between 11/1999 and 8/2004 were identified through our pharmacy database. Records were reviewed and data collected on those patients who had a S-HSR, defined as symptoms for which drug was discontinued, to P, D, or both. Results. 718 patients received P and 93 received D. 59 received D following treatment with P. The presence of S-HSR for P was 2.2% (16/718 patients) and for D was 9.7% (9/93 patients). 10 patients with S-HSR to P crossed over to D and all nine patients reacting to D had a prior reaction to T for a cross-sensitivity rate of 90% (9/10 patients). Conclusions. Cross-sensitivity of D after P was 90% at our institution. Given the different vehicles used in P and D, it is likely attributed to the taxane moiety. Caution is required with re-challenge of patients with docetaxel if they have previously reacted to paclitaxel.

Evaluation of Re-Challenge in Patients with Suspected Lidocaine Allergy

Background: Lidocaine is an anaesthetic agent used worldwide in various clinical specialties. Although lidocaine hypersensitivity is very rare, clinicians frequently encounter patients with such an alleged diagnosis. Using a questionnaire, we evaluated the results of re-challenge with lidocaine, the gold standard for assessing hypersensitivity reactions in patients who claim to be allergic to this drug. Methods: A detailed questionnaire was sent to members of the French Dermatological Society, targeting the management of patients claiming lidocaine intolerance. After analysis and recall of doubtful episodes, 199 re-challenges were made. True lidocaine hypersensitivity was finally demonstrated in only 1 patient. Conclusions: The results of this study demonstrate that patients claiming to be allergic to lidocaine are usually not, their symptoms corresponding in most cases to a vasovagal episode. Re-challenge is safe and may constitute an easy and cheap alternative to skin testing. This should be performed in specialized centres except in case of a vasovagal episode.

Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms

Background: There have been reports from physicians in clinical practice that up to 30% of patients taking bisphosphonate therapy develop upper gastrointestinal (UGI) symptoms, many or most of which they assume to be related to the drug. However, in several large placebo-controlled clinical trials of bisphosphonates, the incidence of UGI symptoms has been ≥30%, even among patients receiving placebo, perhaps reflecting a high background incidence of UGI events in osteoporotic patients. Objective: To assess the relationship between alendronate treatment and UGI complaints in patients who had discontinued treatment with alendronate in clinical practice because of UGI symptoms, we compared the incidence of such events on rechallenge with alendronate or placebo. Methods: This was a multicenter, double-blind trial in which postmenopausal women with osteoporosis who had previously discontinued alendronate therapy because of a UGI adverse experience were randomized to daily treatment with either alendronate 10 mg or matching placebo (1:1 ratio) for 8 weeks. The primary end point was the cumulative incidence of discontinuations due to any UGI adverse experience. Secondary end points were the incidence of any clinical adverse experiences and the percentage change from baseline in urinary N-telopeptide adjusted for urinary creatinine at week 8. Results: A total of 172 women were included in the study. They were a mean of 20.9 years past menopause, ranging in age from 41 to 90 years (mean, 67.0 years); 90.7% were white. On rechallenge, 14.8% ( 13 88 ) of patients in the alendronate group and 16.7% ( 14 84 ) in the placebo group discontinued treatment because of UGI adverse experiences. Conclusion: The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy.

The rechallenge of patients who previously discontinued alendronate due to upper gastrointestinal symptoms

The rechallenge of patients who previously discontinued alendronate due to upper gastrointestinal symptoms

The rechallenge of patients who previously discontinued alendronate due to upper gastrointestinal symptoms

The rechallenge of patients who previously discontinued alendronate due to upper gastrointestinal symptoms

The effectiveness of desensitization versus rechallenge treatment in HIV-positive patients with previous hypersensitivity to TMP-SMX: a randomized multicentric study

Our study was undertaken to evaluate if desensitization treatment is more effective than rechallenge in preventing hypersensitivity reactions in HIV-positive patients with previous allergic reactions to TMP-SMX; the secondary aim was to evaluate the frequency of reactions to TMP alone. This was a randomized, multicentre open study. Patients with previous documented hypersensitivity to TMP-SMX who required primary or secondary PCP prophylaxis were enrolled; subjects who had previously had serious adverse reactions to TMP-SMX were excluded. All eligible patients assumed 200 mg TMP for 14 days and in case of no reactions were randomized for desensitization or rechallenge with TMP-SMX. The patients were then followed up by periodical visits for six months. Seventy-three patients were enrolled; 14 subjects (19%) presented reactions on TMP alone during the pre-enrollment phase. The remaining 59 subjects were randomly assigned to the two treatment groups: 34 carried out desensitization (group 1) and 25 rechallenge (group 2) with TMP-SMX. Seven patients in group 1 (20.5%) and seven in group 2 (28%) showed hypersensitivity reactions during treatment; this difference was not statistically significant. No serious reaction occurred in either group. This study showed the comparable effectiveness of the desensitization procedure and rechallenge in patients with a previous, not serious, allergic reaction to TMP-SMX.