Off-label Practices Research Articles

Off-Label Pediatric Medication Prescribing and Dispensing: Awareness and Attitudes among Community Pharmacists: A Questionnaire-Based Study.

Off-label practice in pediatrics requires relentless engagement from all the health professionals involved. Community pharmacists are the last ones in the prescribing-dispensing chain; therefore, they have the key responsibility of verifying the correctness of a treatment. A cross-sectional study was conducted for assessing the awareness and views of Romanian community pharmacists, regarding off-label drugs in the pediatric population, through a 28-item questionnaire comprising five sections of different topics (general knowledge, frequency of prescribing and dispensing off-label medication, views, and attitudes). The sample size was 236 questionnaires with a response rate of 41.11%. A statistical analysis of the obtained data was performed with GraphPad Prism v.9. The results indicate that 55.1% of the community pharmacists have a good general knowledge and awareness regarding the off-label practice, although the legal frame is unclear. The responses highlight a high frequency of prescribing and request of medication for respiratory conditions (45.3%) and antibiotics (23.5%), with a concerning gap regarding the adverse events related to the off-label treatments (56.7%). A very small percentage of pharmacists (7.1%) contact a fellow healthcare professional when encountering an off-label prescription. In conclusion, in addition to the pharmacist's conduct towards the best interest of the patient, there is a clear need to improve the doctor-pharmacist collaboration in order to make an off-label treatment successful.

Perceptions and experiences of community pharmacists with off-label prescribing in the pediatric population.

This study aimed to investigate and provide insight into the prevalence and patterns of off-label drug use in the pediatric population from the perspective of community pharmacists, addressing the existing data gap in a developing setting. A questionnaire-based cross-sectional study was conducted on Albanian community pharmacists in June 2021. The online administered survey explored the participants' demographic details, perceptions, and experiences with off-label prescriptions in pediatric patients. The statistical analysis conducted on the survey data comprised the construction of frequency tables and the application of the chi-square test for independence. Three hundred and thirty-six community pharmacists nationwide completed the survey, out of which 186 (55.3%) were practiced in Tirana, the capital of Albania. Over 80% of surveyed pharmacists (n = 275) had encountered off-label drug prescriptions in pediatric patients, yet only 40% of participants reported dispensing medicines for off-label use. Community pharmacists reported that general pediatricians tended to prescribe off-label medications more frequently than pediatric subspecialists or general practitioners. It was found that off-label prescriptions were more frequently observed among children aged between 2 and 11 years. Antibiotics were the most reported medicines for off-label use in this study mentioned in almost all off-label categories. Prescribing medicines for unapproved uses for the treatment of pediatric patients is present in community settings in Albania. This indicates the need for further data collection and analysis to understand off-label practices in our country's pediatric population comprehensively.

In vitro optimization of crushed drug-sensitive antituberculosis medication when administered via a nasogastric tube.

The incidence of tuberculosis (TB) in intensive care units (ICUs) can be as high as 3% in high-burden settings, translating to more than 7,500 patients admitted to the ICU annually. In resource-limited settings, the lack or absence of intravenous formulations of drug-sensitive antituberculosis medications necessitates healthcare practitioners to crush, dissolve, and administer the drugs to critically ill patients via a nasogastric tube (NGT). This off-label practice has been linked to plasma concentrations below the recommended target concentrations, particularly of rifampicin and isoniazid, leading to clinical failure and the development of drug resistance. Optimizing the delivery of crushed drug-sensitive antituberculosis medication via the NGT to critically ill patients is of utmost importance.

Improving the Effectiveness of Anticoagulant Therapy: The Promise of Factor XI Inhibition

This continuing medical education-accredited symposium, held at the 2023 International Society for Thrombosis and Haemostasis (ISTH) congress in Montréal, Canada, focused on current unmet needs in anticoagulation, especially in the atrial fibrillation (AF) population, and reflected on the promise of the emerging class of Factor XI inhibitors for stroke prevention (SPAF) in susceptible patients. The faculty agreed that, although direct oral anticoagulants (DOAC) have represented a major advance compared with vitamin K antagonists, their utilisation remains suboptimal, often due to the prevailing fear of bleeding in many types of patients. Older age alone can be a reason for withholding anticoagulation, due to the risk and implications of bleeding. Frailty and comorbidities, such as chronic kidney disease (CKD), which can adversely affect the bioavailability of DOACs, are also deterrents to optimal anticoagulant use. Clinicians may try to avoid or mitigate bleeding by inappropriately prescribing low doses of DOACs, an off-label practice that has been found to fail to protect patients from thrombotic risk, without attenuating the risk of bleeding. In addition, the potential for drug-drug interactions and poor adherence also limit the optimal use of DOACs in real-world clinical practice. A recent patient survey focusing on the topic of ‘minor bleeding’, often referred to by clinicians as ‘nuisance bleeding’, and typically not well captured in clinical trials, revealed the far-reaching impact of ongoing problems with bleeding on quality of life, and the possibility that these experiences may deter patients from adherence to their prescribed anticoagulant regimen. Factor XI represents a promising new target for anticoagulation, which may minimise the risk of bleeding by pharmacologically ‘uncoupling’ the clotting pathway, leading to pathological thrombosis from the cascade largely responsible for physiological haemostasis. Phase II research with investigational Factor XI inhibitors has established their antithrombotic and safety potential, and some of these agents may also avoid other practical drawbacks of DOACs. Phase III evaluation of Factor XI inhibition is ongoing in a number of clinical settings.

Venetoclax is safe and tolerable as post-transplant maintenance therapy for AML patients at high risk for relapse.

Relapse is the most common cause of mortality in acute myeloid leukemia (AML) patients after allogeneic stem cell transplant (SCT). Post-SCT maintenance strategies that prevent relapse are desirable but must be well tolerated and convenient to administer. We hypothesized single agent venetoclax (ven) may be an effective maintenance therapy among high relapse risk patients. Between February 2019 and December 2021, we administered post-SCT ven maintenance to 49 AML patients at high-risk for relapse as a prospectively defined off-label practice at our institution. Ven was planned to be administered until 1-year post-SCT. While temporary interruptions were common (67.3% of all patients), of those with >1 year follow up, 22/25 (88%) completed the full year of planned therapy. Cytopenias (40.8%) and gastrointestinal adverse events (34.7%) were the most common toxicities. At 1-year post-SCT, overall survival (OS) and relapse-free survival (RFS) were 70% and 67% respectively. Our experience demonstrates single agent ven is a safe, tolerable, and feasible maintenance therapy that may improve RFS and OS in high relapse risk post-SCT patients.

Off-Label Medication: From a Simple Concept to Complex Practical Aspects.

Off-label use of drugs is widely known as unapproved use of approved drugs, and it can be perceived as a relatively simple concept. Even though it has been in existence for many years, prescribing and dispensing of drugs in an off-label regimen is still a current issue, triggered especially by unmet clinical needs. Several therapeutic areas require off-label approaches; therefore, this practice is challenging for prescribing physicians. Meanwhile, the regulatory agencies are making efforts in order to ensure a safe practice. The present paper defines the off-label concept, and it describes its regulation, together with several complex aspects associated with clinical practices regarding rare diseases, oncology, pediatrics, psychiatry therapeutic areas, and the safety issues that arise. A systematic research of the literature was performed, using terms, such as “off-label”, ”prevalence”, ”rare diseases”, ”oncology”, ”psychiatry”, ”pediatrics”, and ”drug repurposing”. There are several reasons for which off-label practice remains indispensable in the present; therefore, efforts are made worldwide, by the regulatory agencies and governmental bodies, to raise awareness and to ensure safe practice, while also encouraging further research.

Corneal decompensation following intrastromal hydration of corneal wounds with 0.5% moxifloxacin

Many ophthalmologists have adopted the off-label practice of injecting moxifloxacin intracamerally and into the corneal stroma around the incision at the conclusion of surgery for endophthalmitis prophylaxis. The safety and efficacy of intracameral moxifloxacin for routine cataract surgery has been investigated and endorsed by multiple authors, but to our knowledge, potential complications from intrastromal hydration of clear corneal incisions with 0.5% preservative-free moxifloxacin have not been documented. Two consecutive patients underwent surgery for traumatic ocular injuries. The first patient underwent removal of an intralenticular metallic foreign body with cataract surgery and intraocular lens placement. The second patient underwent repair of an extensive corneoscleral laceration with uveal prolapse. Both patients developed toxic anterior segment syndrome and corneal decompensation within 4 days of intracameral injection and intrastromal hydration of corneal wounds with 0.5% preservative-free topical-formulation moxifloxacin for endophthalmitis prophylaxis following surgery. Surgeons should avoid the use of undiluted 0.5% topical-formulation moxifloxacin drugs for intrastromal hydration of clear corneal incisions following intracameral administration to decrease the risk for corneal decompensation and toxic anterior segment syndrome. We recommend using only 0.1% compounded formulations for both intrastromal and intracameral injections or avoiding intrastromal injection altogether.

Physician-reported barriers and challenges to antibiotic prescribing in surgical prophylaxis: a structured systematic review

Abstract Objectives The purpose of the study is to identify and analyse the barriers in surgical procedures where antibiotic dissipation is habitual. Methods Extensive literature search is carried out using different electronic databases (PubMed, Europe PMC, PLoS and Google Scholar) between January 2000 and December 2020. The articles were selected purely based on the inclusion criteria. Only qualitative and cross-sectional studies were selected to reduce the risk of bias. The JBI and AXIS checklists were used to assessed the quality of the enrolled articles. Data extractions were done by using a predesigned standardized data collection form. Key findings A total of 2067 articles were electronically retrieved but only 14 articles met the eligibility criteria. About 15 902 healthcare professionals (HCPs) with an average response rate of 64.7% were pooled for evidence synthesis. The majority of respondents (50%) discussed different barriers in their practice site for surgical antibiotic prophylaxis (SAP) administration. Barriers were categorized into four themes: lack of guideline availability and knowledge, lack of adherence to guidelines, lack of guideline knowledge and adherence and physician perceptions or off-label practices. A total of 723 (56.3%) out of 1282 HCPs from nine different studies reported a lack of adherence to guidelines during the perioperative process. The majority of respondents in three studies, 318 (82%) out of 386 HCPs, reported that physicians’ perceptions play a crucial role in prescribing SAP during surgeries. Conclusion This study concluded that the barriers within the practice site play a decisive role in SAP optimization and therefore all HCPs are recommended to maintain local/standard guidelines and adhere to them while prescribing SAP.

Off-Label Use of Medicines: A Comparative Study on the Regulation of Medicinal Products in Selected European Union Member States

Many governments have implemented a controlled off-label use of medicines as a tool combined with reimbursement decisions, among other policies, to avoid pharmaceutical firms gaming regulatory systems based on the requirement for marketing authorisation. This article aims to compare the drug regulations in selected European Union countries (France, Italy and Germany) in order to identify specific provisions and concrete solutions implemented by them regarding that matter. The employment of an economic analysis of the law as a theoretical framework allows for the identification of the incentives created in the long run by the referred regulations. The scholarly literature identifies a myriad of drawbacks and advantages associated with off-label practices, and a welfare analysis is ambiguous. Off-label practices are a reality; thus, it is advisable to elaborate policy measures in order to address these practices and condition them on some requirements, taking into account that off-label practices imply trade-offs among access to healthcare, protection of public health, competitiveness and innovation in the industry.

A European proposal to regulate off-label prescription in China

Off-label prescription – that is, the use of a medicine for unlicensed uses – is a practice spread worldwide. Therefore, many countries issued specific regulation to establish its requisites, promote safer off-label practices and punish reckless prescriptions. However, China still lacks a proper juridical framework for off-label prescription. This legal void may turn out to be very dangerous for patients, that in this scenario are at greater risk of injury; but also for physicians, whose likelihood of being suited and effectively convicted is also higher. In addition, it discourages pharmaceutical companies to invest in more research in order to turn those off-label uses in on-label ones, since this practice became an easy source of profit without much effort to them. This article intends to propose some legal measures to help China dealing with off-label prescription, inspired by European law, by national legislations from European countries and by guidelines from European scientific associations and regulatory authorities.

No Difference in Force Required for Intraprosthetic Dislocation of Mixed Manufacturer vs Same Manufacturer Dual Mobility Articulations

BackgroundTo avoid the morbidity of removing well-fixed implants during revision surgery, the off-label practice of mixing femoral heads with dual mobility (DM) polyethylene liners from different manufacturers is commonly performed. The resistance to intraprosthetic dislocation, when the inner prosthetic head disengages from the polyethylene bearing, between mixed and same manufacturer constructs remains unknown. MethodsBetween January 2010 and July 2018, 168 DM liners were retrieved. Specimens were excluded for catastrophic wear (n = 14), previously levered-out (n = 17), and cases in legal proceedings (n = 8). Using a validated setup, 129 specimens were uniaxially loaded 100 mm from the femoral head until lever-out failure of the head from the liner. The difference in maximum lever-out force (LOF) was compared for same and mixed manufacturer retrievals (Student t-test). Multivariable regression analysis evaluated the influence of potential confounders (length of implantation, head size, head material, presence of skirt) on LOF. ResultsNinety-seven same and 32 mixed manufacturer DM constructs were tested. The average LOF for same (272.6 ± 68.7 N) and mixed (299.2 ± 89.0 N) manufacturer specimens was not significantly different (P = .08). An inner head size of 22.2 mm was associated with 184.4-N increase in LOF (P < .001), the presence of a skirt was associated with 63.8-N increase in maximum LOF, and head material (ceramic vs metal) did not influence LOF. ConclusionWe found no difference in the force required to lever-out same and mixed manufacturer inner heads from DM liners, suggesting that mixing manufacturers when placing DM articulations on well-fixed femoral stems should not increase the risk of intraprosthetic instability.

Betadine and Breast Implants.

In the fourth quarter of 2017, the US FDA reviewed and approved a request by one of the breast implant manufacturers for a change in the Directions for Use (DFU) that removed warnings regarding the use of Betadine (povidone-iodine [PI] 10% solution, 1% available iodine [Purdue Frederick Company, Stamford, CT], also available in generic formulations [Aplicare, Inc., Meriden, CT]). Previously, in 2000, there were concerns by the FDA that PI would degrade the silicone elastomer shell. This change in the DFU represents an important advance that will benefit patients through the permitted use of PI to reduce the risk of bacterial contamination of implant surfaces. What was formerly an off-label practice can be openly practiced by plastic surgeons as an anti-infective and biofilm-mitigation strategy. PI has an ideal spectrum effect for gram-positive and gram-negative organisms. Gram-positive organisms have been linked to capsular contracture and gram-negative Ralstonia picketti to breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). R picketti is resistant to aminoglycoside antibiotics, but it is susceptible to at least a 50% solution of PI. We believe that the strategy of antisepsis and biofilm mitigation is an integral part of a contemporary approach for breast augmentation. This is beneficial regarding reduction of the risk of surgical infection, capsular contracture, and BIA-ALCL. Outcome data so far indicate that antibiotics/anti-infectives seem to reduce the incidence of these adverse events that lead to reoperation and increased costs. It behooves plastic surgeons to take all actionable steps that enhance the quality of breast implant outcomes and reduce the rate of reoperation.

Lessons From a Backache

Lessons From a Backache

High-Dose Verapamil in Episodic and Chronic Cluster Headaches and Cardiac Adverse Events: Is It as Safe as We Think?

Cluster headache (CH) is a primary headache disorder with relatively effective treatments. Although few sufficiently controlled trials are available, verapamil is recommended as the first-line prophylactic drug for CH by the French Headache Society (with a low level of evidence, level B) and by the EFNS (European Federation of Neurological Societies, level A). Daily doses of more than 480 mg (and up to 1200 mg daily) are frequently used off-label, while 360 mg daily is the only dosage to have demonstrated its effectiveness in a double-blind trial against placebo, and the usual label posology used by cardiologists is 240 mg daily in hypertension. We report the case of a 19-year-old man who was self-reported to our cardiology consultation for dyspnea and asthenia for 18 months. His medical history consisted of CH crisis for 4 years treated by verapamil 720 mg/day for 18 months with relatively good efficiency. His electrocardiogram (ECG) showed a sinus bradycardia at 40 bpm with a first-degree atrio-ventricular block. Evolution was favorable after progressive verapamil discontinuation. Analysis performed on the French Pharmacovigilance Database between July 1, 2000 and December 1, 2014 found four other cases of cardiac adverse events related to high-dose verapamil used in CH prevention (two cases of syncope with complete atrio-ventricular block with verapamil 1200 and 240 mg daily, respectively, one syncope related to sick sinus syndrome with verapamil 360 mg daily, and one case of sinus bradycardia with verapamil 720 mg daily). Although available studies seem to demonstrate an apparent good tolerance, this off-label practice should not be considered as standard of care and requires strict cardiac monitoring, as suggested by the Agence Nationale de Sécurité du Médicament (ANSM) in a recent re-evaluation of the benefit/risk ratio of high-dose verapamil used in CH prevention.

Tenfold Medication Errors: 5 Years’ Experience at a University-Affiliated Pediatric Hospital

Tenfold medication errors are a significant source of risk to pediatric patients. This may be because of wide variations in age, weight, dosing ranges, and off-label practices, but few studies exclusively devoted to examining pediatric 10-fold error have identified the circumstances and mechanisms that lead to such errors. We examined all 10-fold medication errors reported within an academic, university-affiliated pediatric hospital to make recommendations for future initiatives that could improve medication safety in pediatric practice. We retrospectively evaluated all medication-related incident reports submitted to a voluntary safety-reporting database over a 5-year period for reports describing 10-fold medication error. Main outcome measures comprised severity of error, drugs and drug classes involved, 10-fold medication error enablers, mechanisms, and contributing causes. From 6643 medication-related safety reports, 252 10-fold medication errors were identified at a mean reporting rate of 0.062 per 100 total patient days. Morphine was the most frequently reported medication, and opioids were the most frequently reported drug class. Twenty-two reports described patient harm. Intravenous formulations, paper ordering, and drug-delivery pumps were frequent error enablers. Errors of dose calculation, documentation of decimal points, and confusion with zeroes were frequent contributing causes to 10-fold medication error. This study exclusively and comprehensively examined 10-fold medication errors over a prolonged time in pediatric inpatients. We discuss recommendations of vigilance for specific drugs and standardized order sets for opioids and antibiotics, and identify the administering phase of the medication process as a high-risk practice that can result in pediatric 10-fold medication error.

Editorial: Case series and efficacy

Costalat et al.2 present a retrospective case series of 60 patients undergoing angioplasty and stent treatment with the Wingspan stent system and Gateway percutaneous transluminal angioplasty (PTA) balloon for refractory symptomatic intracranial stenosis. Their study population reflects the approved indication for the device under the FDA Humanitarian Device Exemption (HDE) guidelines specifying its use for patients with ≥ 50% intracranial stenosis who experience recurrent ischemic events while receiving antithrombotic therapy. The study aimed to evaluate the efficacy and safety of intracranial angioplasty and stent insertion in this population. The authors conclude that this treatment may be considered the first alternative for cases of failed medical therapy. Do their data justify their recommendation? The authors have chosen as historical comparators the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) and Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) studies, in which the event rates for patients with symptomatic intracranial stenoses treated medically included a 19% risk of recurrent events within 1 year and a 38.2% risk of ipsilateral ischemic recurrent events at 2 years.1,5 The statistics reported by Costalat et al.2 include a technical success rate of 95.2%; a total procedural complication rate of 20.6%, including 4.8% of patients with permanent morbidity and death; and a combined rate of in-stent restenosis and occlusion of 17.4%. Although at face value these numbers look favorable, the authors are comparing apples to oranges. When the combined rate of stroke and vascular death at 30 days is calculated, it is 16.7% (10 of 60) in their series, which is practically identical to the rate of stroke and vascular death at 1 year with aspirin (15%) or warfarin (17%) in the WASID trial. Do retrospective case series add to our understanding of efficacy for a medical device? Although FDA approval of a drug is based on randomized clinical trials demonstrating both safety and efficacy, a medical device can be approved under an HDE in the absence of efficacy data when clinical investigation is deemed infeasible due to the low prevalence of the condition in the population. Since the FDA approval of the Wingspan stent system and Gateway PTA balloon in August 2005, there has been a proliferation of small case series reflecting the growth in enthusiasm for this therapy as well as the growth in the number of neurointerventionalists. The majority of reported case series are gleaned from procedural data bases, lack any contemporary comparator group, and assess efficacy by comparing the authors’ results to historical controls. Although the collective volume of treated patients now number in the thousands, and the therapy has become a standard of care at many neurointerventional centers, volume and practice patterns do not constitute evidence of efficacy. This caveat is underscored by the recent negative results in 2 randomized clinical trials for secondary stroke prevention, “CLOSURE 1” and the Carotid Occlusion Surgery Study (COSS). In the CLOSURE trial,4 an endovascular device for closing a patent foramen ovale (PFO) was not superior to medical therapy alone, and trial recruitment was hampered by the off-label practice of PFO closure in tens of thousands of potentially eligible patients.3 In the COSS trial, extracranial-intracranial bypass surgery failed to provide an additional benefit to aggressive medical therapy alone, due to the much lower than expected stroke rate in the nonsurgical group (http://clinicaltrials.gov/ct2/show/ NCT00029146?term=coss&rank=2 [Accessed June 7, 2011]). In April 2011, the NIH-funded Stenting versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial (http:// clinicaltrials.gov/ct2/show/NCT00576693?term=sammp ris&rank=1 [Accessed June 7, 2011]) halted further recruitment when the 30-day rate of stroke and death of 14% in patients receiving angioplasty and stent placement was significantly greater than the 5.8% rate with aggressive medical therapy alone. Long-term follow-up will continue, but unless safety and efficacy can be established, “the usefulness of angioplasty and/or stent placement is unknown and is considered investigational.”3

Long‐term risk of clinical events from stenting side branches of coronary bifurcation lesions with drug‐eluting and bare‐metal stents: An observational meta‐analysis

To compare the long-term risks of coronary bifurcation lesions treated with side-branch stenting using drug-eluting versus bare-metal stents. Side-branch stenting is an off-label practice, but when needed, the incidence of late adverse events may differ between drug-eluting and bare-metal stents. We systematically searched PubMed, and the National Institutes of Health and Cochrane Registries for studies of coronary bifurcation stenting reporting clinical outcomes over at least 5 months. Data were extracted and cross checked independently by two investigators for inclusion in an observational meta-analysis. Clinical outcomes included major adverse clinical events (MACE), death, myocardial infarction, target vessel revascularization (TVR), and definite stent thrombosis. We used random-effects models and meta-regression in 6,825 subjects from 42 studies. Most (79%) of the heterogeneity in MACE between treatment groups was explained by differences in stent type, side-branch stenting, and length of follow-up. Compared with drug-eluting stents without side-branch stenting, drug-eluting stents with side-branch stenting had a 3% higher incidence of myocardial infarction [95% confidence interval (CI) = 0.3%, 5%, P < 0.05], but no significant increase in MACE, death, TVR, or stent thrombosis. Bare-metal stenting without side-branch stenting had 10% (95% CI = 3%, 16%, P < 0.01) higher MACE, and 10% (95% CI = 4%, 17%, P < 0.01) higher TVR, whereas bare-metal side-branch stenting had 31% (95% CI = 23%, 39%, P < 0.001) higher MACE, and 19% (95% CI = 10%, 28%, P < 0.001) higher TVR. Side-branch stenting has a much smaller impact on long-term MACE with drug-eluting stents compared with bare-metal stents. Although this study does not support routine side-branch stenting, when side-branch stenting is required, drug-eluting stents are associated with less adverse outcomes.

Off-label use of anti-cancer drugs in India: To be or not to be!

Administering drugs outside the terms of their official labeling is called off-label use. In the West, oncologists often use drugs off-label, which offers several advantages especially while treating patients with multiple comorbidities or advanced cancer. The practice of off-label prescribing of anticancer agents in India is not well documented. A survey on prescribing practices of 10 important drugs used in cancer was conducted in March 2010. Ten centers representing all parts of India were identified. One oncologist from each center was contacted by phone or email and explained about the survey. The list of drugs was sent to them by email if they agreed to participate and they were requested to fill all the indications for which these drugs were used in their center. Labeling for each drug was obtained from the Food and Drug Administration (FDA) website. Off-label practice was categorized as those recommended by the National Comprehensive Cancer Network (NCCN) and those without. Nine out of 10 centers agreed to participate in the survey. Four centers responded to the questionnaire. Six out of 10 drugs were used for off-label indications, cisplatin being the most commonly used. All drugs were either used as per FDA labeling or according to the recommendations of NCCN, except for gemcitabine which was used in one center for some indications based on phase II data. Very limited off-label prescribing was found in oncology practice in India. Since off-label use offers several advantages, judicious use of this practice should be encouraged among the oncologists.

What Lies Beneath? A Lesson for the Clinician. Intraoperative Frozen Section Appearance of Persistent Basal Cell Carcinoma after Apparent Cure with Imiquimod 5% Cream

The Food and Drug Administration (FDA) has approved imiquimod 5% cream for the treatment of nonfacial superficial basal cell carcinoma (BCC), and it has increased in popularity as a nonsurgical approach for the treatment of BCC. Its use for the treatment of superficial BCCs on the trunk, neck, and extremities has been documented in the dermatology and family physician literature. Studies of imiquimod for nodular BCC, on the other hand, have demonstrated suboptimal cure rates according to both clinical and histologic criteria, but little is known about the efficacy of imiquimod cream in the treatment of more extensive lesions, more aggressive BCC subtypes, or treatment in higher risk locations like the face, although the off-label practice of treating facial BCCs with imiquimod is not rare.

Elements of the Menstrual Suppression Debate

In this article I review common arguments and frameworks used by participants in the debate about extended use of combined hormonal contraceptives (CHCs; usually oral contraceptive pills) for menstrual suppression. I examine the way in which menstruation is described and the scope of risks considered. I consider the role of the pharmaceutical industry, personal and clinical experience, and concerns about the contraceptive effectiveness of contraceptive formulations with lower doses. I also address public consequences of the debate, including the possibility of inciting a pill scare, and increasing product awareness and off-label practice.