A review of clozapine safety

Clozapine is a distinctive antipsychotic agent, having a unique clinical profile and an idiosyncratic safety profile. More so than with other agents, the weighting of its adverse event profile is critical, in order to counterbalance its clear clinical advantages. The safety issues with clozapine are in a number of areas, some of which are considered medical emergencies and potentially life-threatening. These include haematological (neutropenia and agranulocytosis), CNS (seizures), cardiovascular (myocarditis and cardiomyopathy), metabolic (diabetes), gastrointestinal and neuromuscular. Understanding the safety profile of clozapine allows an informed use of the agent that can maximise its clear clinical benefit and minimise the known risks.     

A review of clozapine safety

Clozapine is a distinctive antipsychotic agent, having a unique clinical profile and an idiosyncratic safety profile. More so than with other agents, the weighting of its adverse event profile is critical, in order to counterbalance its clear clinical advantages. The safety issues with clozapine are in a number of areas, some of which are considered medical emergencies and potentially life-threatening. These include haematological (neutropenia and agranulocytosis), CNS (seizures), cardiovascular (myocarditis and cardiomyopathy), metabolic (diabetes), gastrointestinal and neuromuscular. Understanding the safety profile of clozapine allows an informed use of the agent that can maximise its clear clinical benefit and minimise the known risks.     

A review of the studies of the safety of polydextrose in food.

Polydextrose (CAS no. 68424-04-4) is a water-soluble polymer of glucose that provides to foods the bulk and texture of sucrose. There are two main forms of polydextrose, an acidic form (PD-A) and a neutralized potassium salt (PD-N). Polydextrose is resistant to mammalian metabolic and microbial degeneration, rendering it both low in caloric value and non-cariogenic. Little polydextrose is absorbed intact although some is metabolized by caecal/colonic bacteria. At high enough levels of ingestion, this bacterial metabolism results in flatus, bloating, loose stools and ultimately a frank diarrhoea. Microbial metabolism also produces some volatile fatty acids that are absorbed by the animal and have calorigenic value. The species and dose threshold for persistent loose stools/watery diarrhoea determines the degree of electrolyte loss by the animal. In the dog, an obligate carnivore, sodium-sparing activity by the kidney and concomitant and obligatory calcium reuptake result in a well-defined aetiology of hypercalcaemia and subsequent nephrocalcinosis, particularly for PD-N. Of the species tested, the dog was the most sensitive to this carbohydrate with a no-effect level of 2000 mg/kg body weight/day. Omnivores, including the rat, mouse and monkey, have a no-effect level ranging from 2500 to 10,000 mg/kg body weight/day. No toxicity has been demonstrated in man, although the dose for laxation (to be distinguished from diarrhoea) is approximately 90 g/day (v. sorbitol at 70 g/day). Polydextrose did not show any reproductive toxicity, teratology, carcinogenesis, mutagenicity or genotoxicity. Polydextrose has been approved for food additive use (21 CFR 172.841) in the US, and an "ADI not specified" by the Joint WHO/FAO Expert Committee on Food Additives (JECFA, 1987). It has been approved in over 50 countries around the world and has been used extensively in the diet for over15 years. Specification monographs are published in the Food Chemicals Codex (FCC) (NAS, 1996) and the FAO Compendium (JECFA, 1995). This review provides an overview of the studies and salient data, not previously reported in the scientific literature, which had been submitted to regulatory agencies in support of these approvals.     

A systematic review of the safety of probiotics

Introduction: Gestational diabetes mellitus (GDM), the most frequent medical complication of pregnancy, is associated with several adverse outcomes over the short- and long-term for both mother and offspring. Standard treatment for GDM consists of insulin injections. Oral hypoglycemic agents (OHAs), on the other hand, are still the subject of controversy. Although OHAs are seemingly as efficient as insulin and may provide better quality of life, congenital malformations and unknown long-term effects are still feared.

Areas covered: Recent data on the pharmacokinetics of two OHAs (glyburide and metformin) and their clinical use for GDM are reviewed, with a focus on clinical trials and observational studies comparing insulin with glyburide or metformin (1960 – 2010). The review will provide a comprehensive overview of the pros and cons of OHA usage, an appreciation of OHAs' efficiency for the purpose of controlling glycemia and embryogenetic basics relating to congenital malformations.

Expert opinion: While insulin treatment is an effective therapy for controlling maternal glycemia, it nevertheless requires sufficient education and skills on the part of the patient to manage properly and may cause hypoglycemia, fear and anxiety. Oral treatment as a more user-friendly alternative may thus facilitate the control of GDM in some patients.     

A review of the safety and tolerability of aripiprazole

It seems that the efficacy of aripiprazole for treating schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors. Aripiprazole has also received approval for the treatment of bipolar disorder as adjunctive therapy or monotherapy (manic or mixed episodes) as well as an augmentation therapy of major depressive disorder (MDD) by the US FDA. The overall safety and tolerability of aripiprazole is favorable compared to other atypical antipsychotics across the approved indications. Aripiprazole showed a minimal propensity for clinically significant weight gain and metabolic disruption. However, extrapyramidal side effects, such as akathisia, are reported and may limit its clinical use in some cases, particularly in patients with bipolar disorder and MDD. This review focuses on the tolerability and safety of aripiprazole across a broad spectrum of psychiatric disorders while taking into consideration results from registrational studies as well as findings from studies in the naturalistic setting. In conclusion, whereas the comparative safety and tolerability of aripiprazole has not been systematically evaluated in comparator studies, tolerability and safety issues commonly associated with atypical antipsychotics such as weight gain and metabolic syndrome are less prominent with aripiprazole.     

A systematic review of the safety of kava extract in the treatment of anxiety.

This paper systematically reviews the clinical evidence relating to the safety of extracts of the herbal anxiolytic kava (Piper methysticum). Literature searches were conducted in four electronic databases and the reference lists of all papers located were checked for further relevant publications. Information was also sought from the spontaneous reporting schemes of the WHO and national drug safety bodies and ten manufacturers of kava preparations were contacted. Data from short-term post-marketing surveillance studies and clinical trials suggest that adverse events are, in general, rare, mild and reversible. However, published case reports indicate that serious adverse events are possible including dermatological reactions, neurological complications and, of greatest concern, liver damage. Spontaneous reporting schemes also suggest that the most common adverse events are mild, but that serious ones occur. Controlled trials suggest that kava extracts do not impair cognitive performance and vigilance or potentiate the effects of central nervous system depressants. However, a possible interaction with benzodiazepines has been reported. It is concluded that when taken as a short-term monotherapy at recommended doses, kava extracts appear to be well tolerated by most users. Serious adverse events have been reported and further research is required to determine the nature and frequency of such events.     

A systematic review of the fetal safety of interferon alpha

BackgroundInterferon alpha (IFN) is an effective treatment for a variety of conditions including essential thrombocythemia (ET), chronic myelocytic leukemia, Hepatitis B and C. Because these conditions also occur in women of childbearing age who may become pregnant, information regarding the safety of this medication in pregnancy is essential. This systematic review attempts to summarize all published data on outcome of pregnancies exposed to IFN alpha, trying to differentiate between disease effect and drug effect.MethodsReports on the use of IFN alpha in human pregnancy and reports on essential thrombocythemia (ET) without use of any medication in pregnancy were identified by a systematic search of the medical literature. We were able to locate only case reports of IFN alpha exposure in pregnancy, of whom 40 out of 63 were diagnosed with ET. We also collected randomly 71 cases (more cases were available in the literature) that were diagnosed with ET due to different etiologies, but who had not received any medication in pregnancy.ResultsAmong the 63 IFN alpha exposures in pregnancy, the mean maternal age was 30 ± 6 years and the mean full term babies’ weight was 3096 ± 463 g. Mean gestational age at delivery was 37 ± 3 weeks. There were 55 single and 4 twin pregnancies. No cases of major malformations or stillbirths were reported. There was one case of spontaneous abortion and 13 preterm deliveries (20% of all exposed cases).Among the 71 cases with untreated ET in pregnancy of different etiologies, 46 (65%) had early (within the first 12 weeks of pregnancy) or late (13–20 weeks of gestation) pregnancy loss. There were also 3 cases (4%) of stillbirth and 4 cases (5.6%) of preterm delivery. Only 18 women (25%) delivered healthy term babies.ConclusionsThe results of our systematic review suggest that IFN-α does not significantly increase the risk of major malformation, miscarriage, stillbirth or preterm delivery above general population rates. It is also possible that IFN-α may have a protective effect against pregnancy loss in cases of ET.     

Zanamivir: a review of clinical safety.

Preclinical and clinical studies have clearly demonstrated that zanamivir, a potent and highly selective inhibitor of the influenza A and B virus neuraminidase, has an impressive safety profile. This report describes the safety and tolerability findings from the clinical studies completed up to the 17 July 1998 involving over 6000 adult and adolescent patients from North America, Europe and the Southern Hemisphere. Serious adverse events from an ongoing Japanese clinical programme are also reported. Zanamivir was administered in various dose forms and frequencies and was found to have a comparable safety profile with placebo when given for both the treatment and prophylaxis of influenza-like illness. These findings were independent of age and underlying medical condition. 4152 patients received zanamivir and the most commonly reported adverse events were consistent with the signs and symptoms of influenza-like illness. Most of the adverse events were mild and did not result in patient withdrawal from the studies. Less than 1% of zanamivir and placebo recipients reported a serious adverse event. In addition, 490 healthy volunteers received zanamivir in clinical pharmacology studies. It was well tolerated and the incidence of adverse events was similar in zanamivir and placebo recipients. In addition, no clinically significant laboratory abnormalities were detected. Results from in vitro and in vivo animal studies suggest that zanamivir has low acute toxicity and no significant systemic toxicity or respiratory tract irritancy at plasma exposures more than 100-fold higher than those anticipated following clinical use. Neither genotoxic nor reproductive types of toxicity have been observed in toxicology studies at doses equal to 17 to 197 times the current therapeutic dose (20 mg/day). The characteristics of the molecule and the low systemic exposure indicate a very low potential for drug interactions with the inhaled route. Furthermore, repeated 600mg intravenous doses were well tolerated in healthy volunteers. The observed safety profile of zanamivir compares favourably with currently available agents with anti-influenza virus activity, such as rimantadine and amantadine, as well as GS4104, a neuraminidase inhibitor currently in phase III development. This may be attributed to the low systemic bioavailability of zanamivir, which is given by oral inhalation, direct to the primary site of viral replication. The potential advantages of this include a reduced risk of drug-drug interactions, other nontarget organ toxicities (e.g. brain) and drug clearance issues from both kidney and liver. Therefore, the safety profile of zanamivir supports its use in the management of influenza.     

A safety review of the medications used to treat atopic dermatitis

Introduction: Atopic dermatitis (AD) is a common disease in children and adults which causes severe physical discomfort and psychosocial distress. Recently novel therapies for AD have been FDA approved for use which creates the need to review the safety surrounding current FDA approved AD medications.

Areas covered: Published clinical studies involving topical and oral FDA approved medications for AD are included in this review. Authors used PubMed research database to search for clinical trials involving AD patients.

Expert opinion: AD is a common disease which currently has limited FDA approved medications. Given the chronicity of this disease, medications are needed which control disease while minimizing side effects to allow for long term use. Newer approved medications show promise but safety data is limited given their relatively new utilization for AD.     

Denatonium benzoate: review of efficacy and safety.

The efficacy and toxicity studies on denatonium benzoate are limited and may be subject to varying interpretations when viewed in the context of a potential poisoning situation. Efficacy studies to date in children have shown that in a controlled environment, addition of denatonium benzoate to an otherwise palatable liquid will decrease the volume ingested. Important considerations include the fact that the number of studies are small (two utilizing orange juice as the liquid; one using a dilute liquid detergent), and these studies involved single-test situations wherein the liquid was available to the child for a limited period of time. Inadequate data are available to analyze one orange juice study and in the other study, 7 of 30 children took more than one swallow. Depending on the "pleasantness" of the liquid (color, smell, similarity to 'drinkable' liquids in appearance) prior to addition of denatonium, it is possible that children may take more than one swallow. Toxicity data indicate a low toxicity profile. However, there are significant gaps in our knowledge, especially relating to chronic toxicity in humans, teratogenicity, and human hypersensitivity potential. The role of denatonium benzoate in preventing serious poisonings has yet to be defined. Aversive agents such as denatonium should augment but not replace proven methods of poison prevention including parental education and child-resistant closures. When selecting products for inclusion of denatonium benzoate, consideration should be given to the inherent toxicity of the product as well as the potential for long-term human exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thalidomide in human immunodeficiency virus (HIV) patients. A review of safety considerations.

The sedative thalidomide was withdrawn from the market 30 years ago because of its teratogenic and neurotoxic adverse effects. The compound was later discovered to be extremely effective in the treatment of erythema nodosum leprosum, a complication of lepromatous leprosy. This effect is probably due to a direct influence on the immune system, because thalidomide possesses no antibacterial activity. The compound is presently used as an experimental drug in the treatment of a variety of diseases with an autoimmune character, including recurrent aphthosis of nonviral and nonfungal origin in human immunodeficiency virus (HIV) patients. This article reviews the most important chemical and pharmacokinetic properties of thalidomide. The possible mechanisms of the nonsedative effects of thalidomide with respect to the safety of its use in HIV patients are discussed. Because the mechanism of the immunomodulatory effect of thalidomide is unknown, the possibility that the administration of this compound will accelerate the deterioration of the immunological status of HIV patients cannot be excluded. Clinical evidence suggests that thalidomide may aggravate the condition of patients with preexisting peripheral neuropathy. Hypersensitivity reactions to thalidomide may occur more frequently in HIV patients than in other patient groups. Because of the teratogenic activity of thalidomide, reliable contraception must be provided to female patients of childbearing age. Before the introduction of thalidomide therapy to an HIV patient presenting with oral ulcers, a fungal or viral origin of the lesions should be excluded. Thalidomide should not be used in patients with preexisting HIV-related peripheral polyneuropathy, polyradiculopathy or encephalopathy. In patients experiencing a complete remission, the discontinuation of thalidomide treatment and its reintroduction in the case of a relapse are preferable to maintenance therapy.     

A safety review of medications used for labour induction

Introduction: Induction of labour is a commonly performed procedure around the world. There are various medications used for induction including those commonly used for cervical ripening (prostaglandins) and oxytocin. The ideal agent is one that decreases the time to achieving delivery without compromising maternal or neonatal safety. The ‘optimal safe agent’ remains undetermined.

Areas covered: This article reviews the safety of currently used induction agents. Prostaglandins and oxytocin have proven to be effective in labour induction, and their profiles will be reviewed in this article. We discuss the data that supports combining some of the agents. We also cover the safety of medications used for labour induction in setting of a scarred uterus.

Expert Opinion: There is continuous debate about the ideal induction agent: one that balances safety with efficacy. We recommend the practice that there is not one perfect agent for all, and that the clinical scenario and previous obstetric history should be considered before choosing an agent. In the future, pharmacogenomics may show that genetics may affect the individual response and adverse reactions to the various agents.     

A review of the safety of selective serotonin reuptake inhibitors during pregnancy

Antidepressant treatment may be desirable or necessary during pregnancy; however, the benefit of treatment must balance the benefits to the mother with any risk to the developing fetus. In order to make educated, patient‐specific, benefit‐to‐risk assessments, an understanding of possible risks associated with in‐utero antidepressant exposure is important. We reviewed all published cohort‐controlled studies (n=4) and prospective surveys (n=5) regarding SSRI use in pregnancy. Outcomes from over 1000 fluoxetine‐exposed pregnancies, more than for any other antidepressant, indicate that first trimester fluoxetine exposure does not statistically significantly increase risk for spontaneous abortion or major malformation. Outcomes from nearly 300 pregnancies exposed to another SSRI (sertraline, paroxetine, or fluvoxamine) suggest the same conclusion. Following in‐utero SSRI exposure, birthweight, rates of prematurity, and postnatal complications appear similar to control values. Preschool age children exposed to fluoxetine in‐utero show no significant differences from controls in global IQ, language, or behavior; such long‐term data are not available for other SSRIs. The substantial clinical experience with fluoxetine‐exposed pregnancies and the preliminary data regarding other SSRIs is reassuring when considering depression treatment for women of child‐bearing potential. Copyright © 1999 John Wiley & Sons, Ltd.     

A safety review of recent advancements in the treatment of psoriasis: analysis of clinical trial safety data

Introduction: The management of psoriasis can include oral medications and injectable biologics. Safety data of these various treatment options are important to consider when choosing the right treatment for the patient.

Areas covered: This review evaluates the safety of newer treatments approved for psoriasis, including interleukin-(IL)-17 inhibitors, IL-23/p19 inhibitors, ustekinumab, certolizumab pegol and apremilast, using phases III and IV clinical trial data.

Expert opinion: Even as treatment of psoriasis becomes safer, it is important to recognize both common and uncommon adverse effects of treatment. Common adverse effects are similar across treatment options, including upper respiratory infection and injection-site reaction. Serious adverse effects occur less frequently and specific to the psoriasis treatment option, such as inflammatory bowel disease and candida infections with IL-17 inhibitors, tuberculosis with certolizumab pegol, and psychiatric events with apremilast. While IL-23/p19 inhibitors may have a slightly better safety profile than other biologics, long-term data are limited. The conclusions that can be drawn from clinical trial safety data are limited given that many clinical trials are not large enough to detect rare safety events. Data from registries provide important complementary information on long-term safety but there are limitations including a lack of randomized assignment between drug treatments.     

DHA复合物抑癌作用的实验研究

目的 :研究DHA复合物的抑癌作用。方法 :以昆明小鼠为荷瘤鼠研究DHA复合物对H2 2 、S180 、艾氏腹水瘤 3株癌细胞的抑制作用 ;用MTT法研究了DHA复合物在体外对U2 51、SKOV 3、SGC 3种癌细胞的半数肿瘤抑制浓度 (IC50 )。结果 :DHA复合物对H2 2 、S180 、艾氏腹水瘤均有明显的抑制作用 ,抑制率均大于30 % ,且具有显著性差异 (P <0 .0 5 )。DHA复合物在体外对U2 51、SKOV 3、SGC 3种癌细胞IC50 分别为 1.2 8,1.0 2 ,1.39均小于 10mg·L- 1。结论 :DHA复合物在体内和体外对癌细胞均有抑制作用     

The safety of rapid infusion levetiracetam: A systematic review

Epilepsy is a common diagnosis and can quickly progress to status epilepticus which requires rapid treatment. Levetiracetam is a frequent treatment choice in these situations. The approved administration of intravenous levetiracetam is an infusion over 15 min. In recent years, studies have been published on faster infusion rates of levetiracetam. The objective of this review is to discuss the safety of levetiracetam as an intravenous push at a rate quicker than recommended. A literature search using PubMed, Cochrane Library, ClinicalTrials.gov , and Google Scholar resulted in 192 articles. Inclusion criteria consisted of English language, human studies, use of levetiracetam administered intravenously at a rate faster than 15 min, discussion of safety, and full-text availability. After screening, nine articles remained for inclusion. Of the nine articles, one was a prospective, open-label study, six were retrospective studies, and two were open-label, randomized controlled trials. The most common rapid infusion speed was 5 min and doses ranged from 280 to 4500 mg. Some of these trials used undiluted levetiracetam and many reported that peripheral access was used for a portion or all of the administrations. There were few adverse effects, including specific adverse effects relating to medication concentration and speed of infusion, in all the studies. Administration of intravenous levetiracetam at a rate faster than recommended in the labeling information appears to be safe and tolerable and can be given via a peripheral line. Rapid infusion of levetiracetam is a beneficial method of administration in an acute care setting where patients need rapid attainment of therapeutic levels of antiepileptic medications. Additional research is needed to ensure that rapid administration of intravenous levetiracetam is as efficacious as the traditional dosing method.     

A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma

Introduction: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases.

Areas covered: A literature search on ‘HDAC inhibitors’ and ‘multiple myeloma’ was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data.

Expert opinion: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.     

A critical review of the safety and antiemetic efficacy of delta-9-tetrahydrocannabinol

Over the past six years, both government institutions and private enterprise have expressed great interest and activity in the isolation of chemical constituents from the Cannabis sativa plant and synthesis of novel cannabinoid compounds with potential medicinal uses. Evaluation of the safety and antiemetic efficacy of delta-9-tetrahydrocannabinol, the primary psychoactive cannabinoid component of marijuana, comprises one of several very active areas of cannabinoid clinical research. The results of clinical studies of the safety and antiemetic efficacy of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy are critically evaluated. Deficiencies in current knowledge of the clinical pharmacology of delta-9-tetrahydrocannabinol are discussed in the context of antiemetic drug evaluation.     

Quetiapine: a review of its safety in the management of schizophrenia.

Quetiapine, a dibenzothiazepine derivative, is a atypical antipsychotic which has greater in vitro binding affinity for serotonin 5-HT2 receptors than for dopamine D2 receptors. Quetiapine effectively treats both the positive and the negative symptoms of schizophrenia and is also associated with an incidence of extrapyramidal symptoms no greater than placebo across the entire dose range. In addition, it does not cause persistent hyperprolactinaemia. Quetiapine is associated with high levels of patient acceptability and satisfaction, which may result from its combination of efficacy and relatively benign adverse effect profile. The drug is well tolerated and has a low propensity to cause adverse events both during acute and long term treatment in the adult populations. The adverse effect profile of quetiapine makes the drug advantageous for patient populations who are susceptible to the adverse effects of drugs. Indeed, preliminary data show quetiapine to be very well tolerated in the elderly. Overdoses of quetiapine of up to 20g have been reported; however, with appropriate management in an intensive care setting there have been no reported fatalities. Quetiapine is metabolised by the cytochrome P450 3A4 isoenzyme, and the dose may need to be adjusted if quetiapine is co-administered with drugs which affect the activity of this isoenzyme. Overall, quetiapine has a favourable risk-benefit profile that should make it a valuable first-line agent in the treatment of schizophrenia.