FDA labeling system for drugs in pregnancy.

OBJECTIVE: To review the current Food and Drug Administration (FDA) pregnancy labeling system, examine the new FDA-proposed pregnancy labeling system for form and content, and provide comments on its suitability for implementation. DATA SOURCES: Data were obtained from the FDA's Web site (www.fda.gov), PubMed, Federal Register, LexisNexis, Physician's Desk Reference (PDR), Drugdex, and Current Contents. STUDY SELECTION: Research and articles involving drugs and pregnancy, drugs and lactation, and the subcommittee meeting of the FDA were included. DATA EXTRACTION: Prospective, case-control studies from pregnancy registries. DATA SYNTHESIS: Currently, only 40% of drugs in the PDR have pregnancy categories listed. The medical profession has resorted to other means to assess pregnancy risk, such as retrospective chart review, case reports, and consultation with experts such as regional drug information centers. CONCLUSIONS: The proposed pregnancy labeling system strives for more clinical usefulness by reliance on human data derived from pregnancy registries. The clinical usefulness of the new labeling remains to be seen.     

中药注射剂不良反应／不良事件的反思

中药注射剂是一类主要在中国大陆地区临床实践中被广泛使用的重要新药。然而最近一段时间,中药注射剂不良反应/不良事件的报告备受关注,甚至有专家提出禁止使用中药注射剂。对此,我们认为应该认真研究,正确对待。我们建议,首先应明晰不良反应和不良事件的概念,以助于鉴别安全性事件;其次,提高中药注射剂注册和审批要求,加强基础研究,更加重视中药注射剂的循证研发和审批;第三,加强中西药相互作用的基础研究;第四,明细中药注射剂审批机构、生产企业、医生和患者的法律责任;第五,加强对卫生保健人员使用中药注射剂的培训;第六,加强监控中药注射剂使用说明书的质量。     

Oral bexarotene in the treatment of cutaneous T-cell lymphoma

OBJECTIVE: To review the preclinical and clinical information related to oral bexarotene approved by the Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. DATA SOURCES: Literature accessed through MEDLINE (from 1990 to July 2000) and provided by the manufacturer. Key search terms included bexarotene, Targretin, LGD1069, and cutaneous T-cell lymphoma. DATA SYNTHESIS: The management of CTCL remains controversial due to its rarity in the US and its heterogeneity. An evaluation focusing on the pharmacology of bexarotene and its role in the management of the different stages of CTCL was conducted. CONCLUSIONS: Bexarotene has demonstrated activity in the treatment of CTCL. The oral route of administration and the adverse effect profile of bexarotene appear to make this drug a favorable option for the treatment of CTCL. Compared with other systemic therapies. Phase III randomized studies are needed to determine the clinical benefits of bexarotene as monotherapy or combination therapy in the treatment of CTCL.     

中药注射剂不良反应及临床合理用药

我国中药注射剂（traditional Chinese medicine injection,CMI）的不良反应涉及国家批准的109个品种。主要不良反应（ADR）包括全身过敏反应、过敏性休克、急性血管内溶血、肝肾功能损害、皮肤损害、心功能损害、呼吸系统损害、胃肠道反应等。引起药物ADR的因素包括：医务工作者对CMIADR重视度不够、中药注射液成分复杂、过敏反应物质不确定、患者特殊体质,尤以儿童和老年人不合理用药现象较重。因此,应从合理选择药物适应症、把握用药方法、避免加大药物浓度、不能随意增加用药剂量和改变用药途径、选择合适的溶媒等方面加强CMI的临床合理使用,减少ADR发生。     

Epoetin-associated pure red cell aplasia: past, present, and future considerations

BACKGROUND: Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin-associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers. STUDY DESIGN AND METHODS: Data on erythropoietin (EPO)-associated PRCA were obtained from the Food and Drug Administration (FDA), regulatory authorities in other countries, and the manufacturers of epoetin alfa, epoetin beta, and darbepoetin. The data included information on numbers of PRCA cases and estimated exposure-adjusted incidence rates by EPO product, anemia etiology, administration route, country of PRCA identification, and date reported. RESULTS: In 1999, academicians in Paris identified 12 EPO-treated patients with antibody-mediated PRCA; 11 of these patients were on hemodialysis and had received subcutaneous Eprex (Johnson & Johnson). In 2002, authorities in Europe, Australia, Singapore, and Canada mandated Eprex by IV route to hemodialysis patients, and the relevant manufacturers added Teflon coating to prefilled syringes of Eprex; PRCA cases subsequently decreased by 90 percent. By 2003, 180 Eprex-associated PRCA cases were identified in Europe, Canada, Australia, and Asia, despite improvements in handling. Since 2002, FDA safety databases include information on 59 new cases of antibody-associated PRCA, primarily associated with subcutaneous epoetin alfa and darbepoetin that does not contain HSA. CONCLUSION: Independent actions by regulatory authorities, manufacturers, and academic researchers identified significant numbers of PRCA cases between 1998 and 2003 and characterized the probable etiology. Today, antibody-mediated PRCA is an infrequent class toxicity occurring among some hemodialysis patients on EPOs.     

Intrathecal Therapy: What Has Changed With the Introduction of Ziconotide

Administering drugs into the intrathecal space is becoming more popular in the treatment of patients with intractable pain or intolerable side effects of systemic analgesic treatments. Although morphine and ziconotide are the only intrathecal analgesics currently approved by regulatory authorities in the U.S. (Food and Drug Administration) and Europe (national-level approval by individual countries for morphine and European Agency for the Evaluation of Medicinal Products approval for ziconotide), a wide variety of opioid and non-opioid drugs are being used in this way. There is no official guidance concerning the selection of these drugs or their use in combinations and a paucity of efficacy and safety data from randomized controlled trials. The polyanalgesic initiative aims to summarize the current knowledge and to facilitate rational choices of intrathecal drug and drug combinations for the management of chronic pain. The most recent polyanalgesic consensus recommendations were published in 2007. In this review, we shall examine these recommendations, which are tailored toward those practicing intrathecal analgesia in the U.S., and discuss how they should be implemented in Europe, where the healthcare systems and regulations of the medical authorities are different.     

FDA policy on unapproved drug products: past, present, and future

OBJECTIVE: To review the history of drug regulation by the Food and Drug Administration (FDA) as it relates to unapproved drugs and FDA policy, along with the FDA's efforts to avoid future incidents by amending and enforcing those policies that are already in place. DATA SOURCES: Data from FDA history documents, FDA guidances, Code of Federal Regulations Title 21, and presentations by the FDA's Office of Compliance were gathered. STUDY SELECTION AND DATA EXTRACTION: All information identified from the data sources was evaluated, and all information deemed relevant was included for this review. DATA SYNTHESIS: Contrary to popular belief, there are drugs on the market that have not been evaluated for safety or efficacy by the FDA. For almost a century, the FDA has taken action against public health threats posed by unapproved drug products, and today's drugs and vaccines are required to demonstrate both safety and efficacy prior to marketing. The FDA has taken great strides to ensure the welfare of Americans by reacting to disasters that have occurred in the past and being proactive by setting regulations that will prevent such catastrophes from occurring in the future. CONCLUSIONS: The FDA recognizes that drug regulation is an ongoing process and that, although we have come a long way, there is still much to be done.     

Sublingual nifedipine controversy in drug delivery

Nifedipine, given sublingually, has become increasingly common for treatment of cardiovascular crises. While this may seem an expedient and safe method to reduce blood pressure, controversial issues have surfaced that emphasize the need for cautious drug delivery. Moreover, sublingual administration of nifedipine is not currently approved by the Food and Drug Administration.     

Recombinant human activated protein C for use in severe sepsis

OBJECTIVE: To review the efficacy and safety of drotrecogin alfa (recombinant human activated protein C) in the treatment of sepsis. DATA SOURCES: Literature was identified through a MEDLINE search (1966-January 2002), the product manufacturer, and the Food and Drug Administration. STUDY SELECTION/DATA EXTRACTION: All relevant information identified from the data sources was evaluated. DATA SYNTHESIS: Drotrecogin alfa reduces coagulation and inflammation in septic patients. A large placebo-controlled clinical trial (n = 1690) of drotrecogin alfa in severely septic patients demonstrated a reduction in mortality (24.7% vs. 30.8%; p = 0.005), with increased bleeding risks (24.9% vs. 17.7%; p <0.001). Patients with more severe sepsis appeared to gain the most benefit. The complete clinical and economic impact of this agent requires further analysis. CONCLUSIONS: Drotrecogin alfa offers a significant advance in the treatment of severe sepsis. Judicious use in appropriate patients is necessary to control cost and maximize clinical benefits.     

Orlistat use in type 2 diabetes

OBJECTIVE: To review the use of orlistat in type 2 diabetes. DATA SOURCES: A MEDLINE search of the English-language literature (1990-August 2001) was performed using the key terms orlistat, obesity, glucose, and diabetes. DATA EXTRACTION: All articles pertaining to orlistat were considered for inclusion, with emphasis placed on randomized, placebo-controlled, double-blind clinical trials. DATA SYNTHESIS: In April 1999, orlistat was approved by the Food and Drug Administration for the treatment of obesity. Of 13 randomized, placebo-controlled studies, only 2 reported specific data in individuals with type 2 diabetes. Both reported significant weight reduction and improved glycemic control over placebo. CONCLUSIONS: Since weight loss is a difficult goal to achieve in patients with type 2 diabetes, orlistat can be a safe, effective addition to a multidisciplinary approach.     

Clinical pharmacology and pharmacokinetics of amprenavir

OBJECTIVE: To review the pharmacokinetics, pharmacodynamics, drug interactions, and dosage and administration information of amprenavir. DATA SOURCE: An extensive review of the literature (MEDLINE search from 1994 to April 2001) relating to the clinical pharmacology of the HIV protease inhibitors was conducted. Meeting abstracts or full presentations and data submitted to the Food and Drug Administration were also reviewed. STUDY SELECTION AND DATA EXTRACTION: The data on pharmacokinetics, pharmacodynamics, drug interactions, and drug resistance were obtained from in vitro studies and open-label and controlled clinical trials. DATA SYNTHESIS: Like all HIV protease inhibitors, amprenavir interrupts the maturation phase of the HIV replicative cycle by forming an inhibitor-enzyme complex, which prevents HIV protease from binding with its normal substrates (biologically inactive viral polyproteins). Amprenavir has an enzyme inhibition constant (Ki = 0.6 nM) that falls within the Ki range of the other protease inhibitors. Amprenavir's in vitro 50% inhibitory concentration (IC50) against wild-type clinical HIV isolates is 14.6 +/- 12.5 ng/mL (mean +/- SD). Pharmacodynamic modeling indicates that, as is the case with other protease inhibitors, the concentration-response curve for amprenavir plateaus at amprenavir trough values above the IC50 for these isolates. This exposure-activity relationship, plus such favorable pharmacokinetic parameters as a long terminal elimination half-life (7-10 h), makes amprenavir an attractive drug of choice when considering potent antiretrovirals. The higher trough exposure obtained with amprenavir coadministered with ritonavir may allow effective treatment of patients with decreased susceptibility viral isolates and once-daily dosing. Amprenavir has been approved for adults and children; the recommended capsule doses are 1200 mg twice daily for adults and 20 mg/kg twice daily or 15 mg/kg 3 times daily for children < 13 years of age or adolescents < 50 kg. The recommended dose for amprenavir oral solution is 1.5 mL/kg twice daily or 1.1 mL/kg 3 times daily. CONCLUSIONS: The clinical pharmacology, exposure-activity relationship, and drug resistance profile of amprenavir support the use of this potent HIV protease inhibitor in combination antiretroviral regimens, especially for persons who have experienced virologic failure while on protease inhibitor-containing regimens.     

Practical use of rectal medications in palliative care

The rectal route of drug administration is an efficient and economical method for pharmacologic intervention in the terminally ill patient for whom the oral route is precluded. This review first describes the physiology and general considerations surrounding rectal drug administration, then evaluates the literature pertaining to analgesic and adjuvant medications and dosage forms that are and are not approved for rectal administration by the U.S. Food and Drug Administration. A paucity of studies deal with rectal administration in terminally ill patients, and data have been gathered from pharmacokinetic studies or studies in which the drugs were used for other indications. Where plausible, practical clinical recommendations for the rectal use of opioids, nonopioid analgesics, anxiolytics, and other adjuvants are formulated.     

Low-dose granisetron for postoperative nausea and vomiting prophylaxis

OBJECTIVE: To evaluate the use of low-dose granisetron in postoperative nausea and vomiting prophylaxis. DATA SOURCES: Clinical trials available through PubMed and OVID (1966-July 2003), as well as information supplied by the drug manufacturer, were accessed. DATA SYNTHESIS: Safety concerns associated with droperidol and limited availability of other agents have created a need to restructure prophylaxis guidelines for postoperative nausea and vomiting. It has recently been proposed that granisetron may be effective at a dose that is one-tenth of the Food and Drug Administration-approved dose. Conflicting evidence for this regimen is evaluated. CONCLUSIONS: Based on the scarcity of supporting data, this regimen is not recommended for prophylaxis in patients at risk for postoperative nausea and vomiting.     

Establishing clinical utility of pharmacogenetic tests in the post-FDAAA era

The US Food and Drug Administration (FDA) Amendments Act of 2007, when fully implemented, will offer new sources of evidence and new regulatory mechanisms during the postmarket phase of drug life. If artfully and carefully applied, these new capabilities could help resolve problems that have long impeded the clinical translation of pharmacogenomics.     

Predicting inhibitory drug-drug interactions and evaluating drug interaction reports using inhibition constants

OBJECTIVE: To review the use of inhibitory constants (Ki) determined from in vitro experiments in the prediction of the significance of inhibitory drug-drug interactions (DDIs). DATA SOURCES: Searches of MEDLINE (1966-August 2004) and manual review of journals, conference proceedings, reference textbooks, and Web sites were performed using the key search terms cytochrome P450, drug-drug interaction, inhibition constant, and Ki. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated, and information deemed relevant was included for this review. DATA SYNTHESIS: The cytochrome P450 isoenzymes factor prominently in the explanation of numerous DDIs. Although the regulation of these enzymes by one drug can affect the pharmacokinetics of other drugs, the consequences may not necessarily be significant either in terms of pharmacokinetic or clinical outcomes. Yet, many DDI monographs originate as unconfirmed case reports that implicate the influence of one drug on the CYP-mediated metabolism of another, and these often uncorroborated mechanisms can eventually become regarded as dogma. One consequence of this process is the over-prediction of potentially important DDIs. The pharmaceutical industry, Food and Drug Administration, and pharmaceutical scientists have developed a strategy for predicting the significance of inhibitory DDIs at the earliest possible stages of drug development based on a new chemical entity's Ki value, determined in vitro. CONCLUSIONS: We suggest that the use of Ki values of drugs purported to behave as CYP inhibitors be incorporated in the assessment of case reports that ascribe DDIs to inhibition of metabolism of one drug by another.     

Opioid dependence treatment, including buprenorphine/naloxone

OBJECTIVE: To review opioid dependence (OD) and its treatment. Pharmacologic treatments, including the use of buprenorphine/naloxone, are presented. Pharmaceutical care functions for outpatient OD treatment are discussed. DATA SOURCES: Primary and review articles were identified by MEDLINE and HEALTHSTAR searches (from 1966 to November 2000) and through secondary sources. Tertiary sources were also reviewed regarding general concepts of OD and its treatment. STUDY SELECTION/DATA EXTRACTION: Relevant articles were reviewed after identification from published abstracts. Articles were selected based on the objectives for this article. Studies of the treatment of OD with buprenorphine were selected based on the topic (pharmacology, pharmacokinetics, adverse reactions) and study design (randomized, controlled clinical trials in patients with OD with active/placebo comparisons and/or comparisons of active OD treatments). Articles regarding pharmacists' activities in the treatment and prevention of OD were reviewed for the pharmaceutical care section. DATA SYNTHESIS: OD is considered a medical disorder with costly adverse health outcomes. Although methadone maintenance treatment (MMT) is cost-effective for OD, only about 12% of individuals with OD receive this treatment. Psychological and pharmacologic modalities are used to treat OD, but patients often relapse. Drug therapy includes alpha 2-agonists for withdrawal symptoms, detoxification regimens with or without opioids, opioid antagonists, and opioid replacement including methadone, levomethadyl acetate, and buprenorphine. The Drug Addiction Treatment Act of 1999 allows for office-based opioid replacement therapies. Sublingual buprenorphine with naloxone can be used in this milieu. Buprenorphine with naloxone is currently under new drug application review with the Food and Drug Administration. Clinical research shows buprenorphine to be equal in effectiveness to methadone, but safer in overdose due to its ceiling effect on respiratory depression. It has lower abuse potential and fewer withdrawal symptoms when discontinued. Naloxone is included to decrease diversion and injection of the tablets. Pharmacists in outpatient settings who are familiar with OD have opportunities to provide pharmaceutical care to patients receiving this treatment. Pharmaceutical care functions for OD include ensuring appropriate drug administration, monitoring adverse effects, alleviating withdrawal symptoms, treating intercurrent illnesses, minimizing diversion, and preventing relapse. CONCLUSIONS: OD is a critical unmet health problem in the US. Buprenorphine combined with naloxone represents an innovative treatment for OD in outpatient settings. This new treatment has advantages over MMT.     

What Happens to the Old Headache Medicines?

Old headache medicines never die; they either fade away or come back in disguise. The disguise is often a new route of administration, which may work better, faster, more completely, with fewer adverse events, and/or have certain other advantages. The clinical aspects of 3 of the oldest headache medicines (ergotamine tartrate, dihydroergotamine, and methysergide) will be discussed here. Sumatriptan will then be discussed as the prototype of the newest category of acute care therapy (triptans) for migraine. It will be compared with the older medications, and the new forms being developed will be briefly discussed. Diclofenac potassium for oral solution will be mentioned as the newest drug approved for migraine by the Food and Drug Administration, and a possible alternative to triptans in patients with frequent headaches or those with contraindications to vasoconstrictors.     

The Institute of Medicine's report on drug safety: constructive and ambitious, but does it go far enough?

In September 2004, controversy surrounded the Food and Drug Administration (FDA). It climaxed more than a decade of safety concerns involving legitimate and perceived problems with FDA-approved drugs. In response, the FDA's Center for Drug Evaluation and Research (CDER) asked the Institute of Medicine (IOM) to examine the current systems for ensuring drug safety and recommend specific actions and improvements.     

The history and contemporary challenges of the US Food and Drug Administration

BACKGROUND: The year 2006 marks the 100th anniversary of the regulatory agency now known as the US Food and Drug Administration (FDA), the first consumer protection agency of the federal government and arguably the most influential regulatory agency in the world. The FDA thus plays an integral role in the use of pharmaceuticals, not only in the United States but worldwide. OBJECTIVE: The goal of this review was to present an overview of the FDA and place its current role in the perspectives of history and contemporary needs. METHODS: Relevant materials for this review were identified through a search of the English-language literature indexed on MEDLINE (through 2006) using the main search terms United States Food and Drug Administration, FDA, history of the FDA, drug approvals, drug legislation, and FDA legislation. Results from the initial searches were then explored further. RESULTS: The statute that created the bureau which later became the FDA established this agency to prohibit interstate commerce of adulterated foods, drinks, and drugs. The Food, Drug, and Cosmetic Act that replaced it in 1938, and subsequent food and drug laws and amendments, expanded the FDA's responsibilities to cosmetics, medical devices, biological products, and radiation-emitting products. These amendments have also established the FDA as a mainly preventive regulatory agency that relies chiefly on pre-market control. As such, the FDA has played an important role in shaping the modern pharmaceutical industry by making the scientific approach and the clinical trial process the standard for establishing safety and efficacy and by making rigorous scientific analysis the predominant component of the process for pharmaceutical regulation. CONCLUSIONS: As shown in this review, the evolution of the FDA can be described as a series of "crisis-legislation-adaptation" cycles: a public health crisis promoted the passage of congressional legislation, which was then followed by implementation of the law by the FDA. However, the crises the FDA faces currently are likely to be overcome only under strong and permanent leadership willing to redefine the role and procedures of the FDA with an open mind.