Vinita B. Pai

Cardiotoxicity of Chemotherapeutic Agents

Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide, the vinca alkaloids, fluorouracil, cytarabine, amsacrine, cladribine, asparaginase, tretinoin and pentostatin. Cardiotoxicity is rare with some agents, but may occur in >20% of patients treated with doxorubicin, daunorubicin or fluorouracil.Cardiac events may include mild blood pressure changes, thrombosis, electrocardiographic changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure) and congestive heart failure. These may occur during or shortly after treatment, within days or weeks after treatment, or may not be apparent until months, and sometimes years, after completion of chemotherapy.Anumber of risk factors may predispose a patient to cardiotoxicity. These are: cumulative dose (anthracyclines, mitomycin); total dose administered during a day or a course (cyclophosphamide, ifosfamide, carmustine, fluorouracil, cytarabine); rate of administration (anthracyclines, fluorouracil); schedule of administration (anthracyclines); mediastinal radiation; age; female gender; concurrent administration of cardiotoxic agents; prior anthracycline chemotherapy; history of or pre-existing cardiovascular disorders; and electrolyte imbalances such as hypokalaemia and hypomagnesaemia. The potential for cardiotoxicity should be recognised before therapy is initiated. Patients should be screened for risk factors, and an attempt to modify them should be made.Monitoring for cardiac events and their treatment will usually depend on the signs and symptoms anticipated and exhibited. Patients may be asymptomatic, with the only manifestation being electrocardiographic changes. Continuous cardiac monitoring, baseline and regular electrocardiographic and echocardiographic studies, radionuclide angiography and measurement of serum electrolytes and cardiac enzymes may be considered in patients with risk factors or those with a history of cardiotoxicity.Treatment of most cardiac events induced by chemotherapy is symptomatic. Agents that can be used prophylactically are few, although dexrazoxane, a cardioprotective agent specific for anthracycline chemotherapy, has been approved by the US Food and Drug Administration. Cardiotoxicity can be prevented by screening and modifying risk factors, aggressively monitoring for signs and symptoms as chemotherapy is administered, and continuing follow-up after completion of a course or the entire treatment. Prompt measures such as discontinuation or modification of chemotherapy or use of appropriate drug therapy should be initiated on the basis of changes in monitoring parameters before the patient exhibits signs and symptoms of cardiotoxicity.

Bruising Associated with the Use of Fluoxetine

OBJECTIVE: To report a case of suspected fluoxetine-induced bruising and review the literature surrounding this rare adverse effect. CASE SUMMARY: A 31-year-old white woman was diagnosed with depression and treated with fluoxetine. After fluoxetine 20 mg/d for 6 weeks, she reported bruising that was disproportionate to any trauma incurred. Her prothrombin time, partial thromboplastin time, and complete blood cell count were within normal limits. Fluoxetine was suspected to be the cause of this bruising. The patient did not want to discontinue the medication and has continued to bruise while continuing fluoxetine therapy. DISCUSSION: Frequently encountered adverse effects caused by fluoxetine use include nausea, nervousness, and insomnia, but hematologic effects have also been reported. These include bleeding or bruising with prolonged bleeding time, increased prothrombin time and partial thromboplastin time, and thrombocytopenia. The mechanism behind these adverse effects is the prevention of serotonin-induced amplification of platelet aggregation by fluoxetine. Blockade of 5-hydroxytryptamine uptake in the platelets by fluoxetine reduces or depletes the platelet serotonin stores, thereby predisposing a patient with a mild underlying platelet disorder to a fluoxetine-induced hematologic disorder. CONCLUSIONS: Fluoxetine has been reported to produce bruising, bleeding, and other hematologic disorders. It should be used with caution when treating patients with thrombocytopenia or with proven or suspected platelet dysfunction.

Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation.

Anti‐seizure prophylaxis is routinely utilized during busulfan administration for HSCT. We evaluated the feasibility and efficacy of levetiracetam in children undergoing HSCT. A total of 28 children and young adults received levetiracetam during HSCT and the outcomes and costs were compared to a historical, but similar cohort of 25 patients who had received fosphenytoin. Levetiracetam was well tolerated and was efficacious in preventing seizures. Cost of drug, administration, and monitoring were also similar among the two groups. Due to non‐induction of the hepatic cytochrome P450 enzymes, levetiracetam may lead to better dose assurance of busulfan in targeted dose regimens for HSCT. Pediatr Blood Cancer 2012;59:762–764.

Conjugated Heptavalent Pneumococcal Vaccine

OBJECTIVE: To review the immunogenicity, efficacy, and safety of the heptavalent conjugated pneumococcal vaccine (PCV7). DATA SOURCES: A MEDLINE search (1993–August 2001) of research limited to humans published in the English language was conducted. STUDY SELECTION: Findings from randomized, controlled, multicenter trials were reviewed. Literature regarding epidemiology, control, and treatment of invasive pneumococcal diseases in different populations and the Advisory Committee on Immunization Practices recommendations were also reviewed. DATA SYNTHESIS: PCV7 administered to infants aged 2, 4, and 6 months, with a booster dose at 12–15 months, has been shown to be immunogenic. It decreases the incidence of invasive pneumococcal disease; individual data on bacteremia and meningitis are unavailable. Findings from clinical trials showed that invasive pneumococcal disease caused by vaccine serotypes was reduced by 87%, 58%, and 62% for children <1 year, <2 years, and <5 years of age, respectively, after introduction of routine vaccine use. The overall incidence of acute otitis media did not decrease significantly. However, culture-confirmed episodes and episodes due to pneumococcal serotypes included in the vaccine were reduced. The vaccine was immunogenic in children with sickle cell disease, but its efficacy in preventing invasive pneumococcal diseases remains unclear. Although immunogenicity and efficacy trials are lacking, the vaccine is recommended for Alaskan Native or American Indian children between 24 and 59 months of age, and for children with underlying conditions such as HIV infection, AIDS, other immunocompromising conditions, and chronic illnesses. At the manufacturers list price of

Busulfan and melphalan as consolidation therapy with autologous peripheral blood stem cell transplantation following Children's Oncology Group (COG) induction platform for high-risk neuroblastoma: early results from a single institution.

58/dose, PCV7 is not projected to be cost-effective after 4 doses. Postmarketing analysis evaluating immunogenicity and efficacy in the excluded population may favorably change this. CONCLUSIONS: Based on published efficacy and immunogenicity data, pharmacy formularies should include PCV7.

Octreotide acetate is efficacious and safe in children for treating diarrhea due to chemotherapy but not acute graft versus host disease.

Bu‐Mel as preparative therapy prior to autologous stem cell rescue was recently shown to be superior to the conventional CEM regimen for HR NBL in Europe. There are no data available on the feasibility and toxicity of Bu‐Mel as consolidation therapy following the COG‐type induction regimens used in North America. We report early complications and outcomes of patients with HR NBL who received Bu‐Mel for consolidation following COG‐based induction. Retrospective analysis of all patients who had received Bu‐Mel as preparative regimen prior to stem cell rescue for HR NBL was carried out. Toxicity, outcomes, and any delays to receiving radiation or anti‐GD2 antibody therapy were analyzed. Six patients undergoing PBSCT had received Bu‐Mel. The treatment was well tolerated. Mucositis was the main toxicity; three patients had developed neutropenia fever and none developed pulmonary toxicity. One patient had developed moderate SOS that responded to conservative management. All patients were able to receive and tolerate post‐transplant local radiotherapy and ch.14.18 anti‐GD2 antibody therapy without any delays. All patients are alive with no disease recurrence. The Bu‐Mel regimen is well tolerated and is feasible post‐COG‐type induction platform.

Twice daily i.v. bolus tacrolimus infusion for GVHD prophylaxis in children undergoing stem cell transplantation.

The Common Toxicity Criteria of the National Cancer Institute evaluates diarrhea as an adverse event of chemotherapy administration. Acute graft versus host disease (aGVHD) causes diarrhea in allogeneic hematopoietic stem cell transplant patients. Guidelines for treating grade 3 and 4 chemotherapy induced diarrhea (CID) include octreotide acetate, a somatostatin analogue. These recommendations are based on adult octreotide trials. Data on octreotide use for treatment of CID in pediatric oncology patients are limited. This study evaluated the efficacy and safety of octreotide in the treatment of CID or aGVHD induced diarrhea in pediatric patients.

Impact of a Pharmacy Student-driven Medication Delivery Service at Hospital Discharge

Tacrolimus is routinely administered for GVHD prophylaxis as a 24-h continuous infusion that requires a dedicated i.v. line and thus becomes logistically difficult to administer, especially in young pediatric patients. We investigated the safety and efficacy of twice daily bolus infusions of i.v. tacrolimus in 33 children undergoing hematopoietic stem cell transplantation (HSCT) at our institution. Tacrolimus was started at an initial dose of 0.015 mg/kg i.v. bolus administered as a 2-h infusion and then given at every 12 h to maintain a trough drug level between 5–15 ng/mL. Patients also received short-course MTX (66%) or mycophenolate mofetil (34%) in combination with tacrolimus. No acute infusional toxicities were observed with bolus infusions of i.v. tacrolimus. Nephrotoxicity occurred in 14/33 (42%) patients and 48% developed hypertension (HT). Almost all (94%) patients required magnesium supplements to maintain magnesium (Mg) levels ⩾1.5 mg/dL. In all, 3 (9%) patients developed severe sinusoidal obstruction syndrome (SOS). One patient developed posterior reversible leuko-encephalopathy syndrome (PRES) and one additional patient had tremors. The prevelance of these side-effects was similar to those reported for continuous i.v. administration. In all, 28% of the evaluable patients developed acute GVHD⩾grade II, though the incidence of severe (grade III–IV) GVHD was only 7%. These results suggest that intermittent bolus i.v. tacrolimus administration is a safe and effective method of GVHD prophylaxis in children.

Delayed administration of filgrastim (G-CSF) following autologous peripheral blood stem cell transplantation (APBSCT) in pediatric patients does not change time to neutrophil engraftment and reduces use of G-CSF†

Purpose. A pharmacy student‐driven discharge service developed for patients to reduce the number of medication errors on after‐visit summaries (AVSs) is discussed. Methods. An audit of AVS documents was conducted before the implementation period (September 3 to October 23, 2013) to identify medication errors. As part of the audit, a pharmacist review of the discharge medication list was completed to determine the number and types of errors that occurred. A student‐driven discharge service with AVS review was developed in collaboration with nursing and medical residents. Students reviewed a patients AVS, delivered the discharge prescriptions to bedside, and conducted medication reconciliation with the patient and family. The AVS audit was conducted after implementation of these services to assess the impact on medication errors. Results. It was observed that 72% (108 of 150) of AVSs contained at least 1 error before discharge and AVS review. During the 2‐month postimplementation period (September 3 to October 23, 2014), this decreased to 27% (34 of 127), resulting in a 52% absolute reduction in the number of AVSs with at least 1 medication error (p < 0.0001). The most common error was as‐needed medication with no indication, which decreased from 55% in the preimplementation audit to 16% in the postimplementation audit. Prescribing to Nationwide Childrens Hospitals outpatient pharmacy increased from 57% in the preimplementation period to 73% in the postimplementation period for the general pediatrics service. Conclusion. A pharmacy student‐driven discharge and medication delivery service reduced the number of AVSs and increased access to medications for patients.

Matched unrelated donor transplantation in glycogen storage disease type 1b patient corrects severe neutropenia and recurrent infections

Delayed initiation of granulocyte colony stimulating factor (G‐CSF) after high‐dose chemotherapy and autologous bone marrow or peripheral blood stem cell (APBSCT) in adult patients does not affect time to neutrophil or platelet engraftment, duration of fever, incidence of bacteremia, duration of non‐prophylactic antibiotic therapy, and length of hospitalization when compared to early initiation. This study compares the effect of delayed (day +6) versus early (day +1) administration of G‐CSF in pediatric patients on time to neutrophil engraftment (TNE), duration and cost of G‐CSF therapy, incidence of blood stream infections, duration of febrile–neutropenia, duration of non‐prophylactic antibiotic therapy, and duration of hospitalization due to febrile–neutropenia.