Post-marketing surveillance of the safety of cimetidine: twelve-month morbidity report

A total of 9928 patients taking cimetidine and 9351 controls were included in a post-marketing drug surveillance study in Glasgow, Nottingham, Oxford and Portsmouth; 98.8 per cent of the takers and 97.7 per cent of the controls were successfully followed up for at least one year during which hospital visits and deaths were recorded. Methods of identification of subjects and 12-month mortality results have been reported previously. A general analysis of the morbidity experienced by these patients during the study year is presented here. Thirty-nine per cent of takers and 21 per cent of controls were seen at outpatient clinics, and 18 per cent of takers and 8 per cent of controls were admitted to hospital; 15 325 individual diagnoses in takers and 5002 diagnoses in controls were reviewed. An association with cimetidine treatment was found, as expected, for gastrointestinal diseases. Weaker associations were found for haematological disorders, some tumours, infections, disorders of the locomotor system and respiratory diseases. Detailed examination revealed that these were mainly due to confounding from several sources, for example, from the underlying cause of the dyspepsia which resulted in cimetidine use, from the higher level of physician contact in cimetidine takers, and smoking. The scheme successfully detected and quantified some already known adverse effects of cimetidine and did not detect any new effects. It is concluded that this method of collecting information is feasible and useful, but several interpretive pitfalls arise, some of which can be avoided by careful analysis. No evidence of any major unrecognised risk of cimetidine treatment emerged from the study.     

Latest industry information on the safety profile of levofloxacin in Japan

This paper focuses on the development of four major adverse drug reactions (ADRs) associated with some fluoroquinolones: convulsions, phototoxicity, cardiac effects, and hepatotoxicity. CNS adverse events have been linked to fluoroquinolone administration, including seizures, which are more likely with co-administration of NSAIDs. Only 61 cases of convulsions have been reported with levofloxacin, with 33 of those affected having received NSAIDs. The assumed rate of serious convulsions was as low as 1/65,000 with NSAIDs and 1/260,000 without NSAIDs. Levofloxacin has a very low phototoxicity-inducing potential confirmed by pre-clinical animal studies and the results of post-marketing surveillance (PMS). Pre-clinical results demonstrated that levofloxacin was 20 times less phototoxic than sparfloxacin and PMS data show that serious phototoxicity develops in only 1 in 1.8 million cases treated with levofloxacin. While many fluoroquinolones are associated with cardiac effects, pre-clinical data has shown that compared with sparfloxacin and grepafloxacin, levofloxacin has no effect on myocardial conduction. PMS data further support the safety of levofloxacin in this regard. While trovafloxacin is associated with serious hepatic problems, PMS data demonstrates that levofloxacin has a very low incidence of 1/100,000 hepatic effects. These results were confirmed in a prospective study that confirmed a low 1.3% incidence rate for all ADRs associated with levofloxacin.     

Post-marketing surveillance of the Transiderm-Nitro patch in general practice

Post-Marketing Surveillance (PMS) of Transiderm-Nitro, a new transdermal form of nitroglycerin, was undertaken during the 6 months following its introduction to general practitioners in the United Kingdom. Two thousand four hundred and seventy-five record forms were received. Excluding the fourteen patients who died during the surveillance, treatment in the remaining 2461 was judged as effective in 80.6% of patients and was well tolerated, with 70.5% having no unwanted effects. The incidences of withdrawal from Transiderm-Nitro in all patients analyzed were 5.7% due to headaches, 3.6% due to other unwanted effects and only 3.1% due to the treatment being judged as ineffective. This PMS confirms that Transiderm-Nitro is an effective, well tolerated addition to the therapy of angina pectoris.     

Post-marketing surveillance of Euhypnos (temazepam): a new hypnotic

A post-marketing surveillance study of Euhypnos (temazepam), a new short-acting benzodiazepine hypnotic. A total of 12,350 patients requiring a sleep inducer were treated for up to 3 months with doses of 10-30 mg at night. After 2 weeks 80% of First Reports (FRs) rated Euhypnos effective and at 3 months this had risen to 92% of 3062 Second Reports (SRs). Hangover was reported in 7% of FRs and 2% of SRs but in general the drug was well tolerated with adverse reactions consisting mainly of morning nausea, headache, drowsiness and vivid dreaming. Eighty-seven per cent of FRs and 93% of SRs were 'Clean' reporting no hangover, adverse reaction or event of any kind.     

Influenza surveillance in Japan

In Japan, under the National Epidemiological Surveillance of Infectious Diseases, clinically diagnosed influenza cases have been reported by approximately 5,000 influenza sentinel clinics and influenza virus isolation have been reported by prefectural and municipal public health institutes (PHIs). Influenza virus strain surveillance have been conducted by PHIs and National Institute of Infectious Diseases for selectin of vaccine strains. Weekly influenza case and influenza virus isolation data have been submitted to WHO FluNet website. In addition, HI antibody prevalence have been monitored by the National Epidemiological Surveillance of Vaccine-preventable Diseases. Various information about influenza surveillance in Japan is available on the Infectious Disease Surveillance Center website (http://idsc.nih.go.jp/iasr/index.html).     

Efficacy and safety of garenoxacin tablets on bacterial pneumonia: Postmarketing surveillance in Japan

We performed a postmarketing surveillance study to determine the efficacy and safety of the oral quinolone antibacterial agent, garenoxacin (Geninax^® Tablets 200 mg), against bacterial pneumonia.Between October 2009 and March 2011, patients with community-acquired pneumonia visited 174 facilities in Japan; we collected survey forms from 739 patients of these patients who were suspected with bacterial pneumonia on the basis of factors, e.g., the presence of purulent sputum or suspected presence of bacterial pathogens in clinical specimens. We examined the safety in 730 patients and the efficacy in 535 patients.The efficacy rate of garenoxacin for bacterial pneumonia was 92.8% (479/516 patients). The eradication rates for Streptococcus pneumoniae and Haemophilus influenzae, the major pathogens of bacterial pneumonia, were 98.5% (65/66 strains) and 100% (65/65 strains), respectively.The incidence of adverse drug reactions (including abnormal laboratory tests) was 7.9% (58/730 patients). Among the main adverse drug reactions, abnormal laboratory tests were observed in 2.1% patients (15/730), hepatobiliary disorders were observed in 1.8% patients (13/730), and skin and subcutaneous tissue disorders were observed in 1.6% patients (12/730).In conclusion, garenoxacin showed an efficacy rate of greater than 90% for bacterial pneumonia and is considered to be useful in daily practice.     

Drug use investigation on the safety and efficacy of tigecycline in Japan (all-case post-marketing surveillance)

IntroductionWe conducted a drug use investigation to investigate the safety and efficacy of tigecycline, which has been approved for clinical use for the treatment of multidrug-resistant gram-negative infections in Japan.MethodsThis was an open-label, observational, multicenter cohort study that included all patients who received tigecycline.ResultsA total of 116 patients were registered between December 2012 and April 2016 and all of them were evaluated for safety and efficacy. Among them, 64 patients aged ≥65 years (55.2%) and five children aged <15 years (4.3%) were included. Of these patients, 47 (40.5%) met the approved indications of tigecycline. Adverse drug reactions (ADRs) were observed in 41 patients (35.3%) with a total of 74 events. Serious ADRs were observed in 15 patients (12.93%) with a total of 33 events. There were 42 deaths, and 6 of these were considered to be caused by ADRs. Among the 116 patients, 65 achieved clinical response at the end of the observation period, and the efficacy rate was 73.9%. Furthermore, 46 patients were assessed as “cure” at the test of cure visit, and the cure rate was 59.0%. The eradication rate was 47.5% at the end of the observation period. Classified by pathogenic bacteria, the eradication rate of patients infected with the approved pathogens was 54.5%.ConclusionsTigecycline was well-tolerated, and no additional safety concerns were noted. It was effective considering that most patients had poor physical conditions. The overall benefit–risk balance of tigecycline was favorable.     

Efficacy and safety of garenoxacin tablets on clinically diagnosed atypical pneumonia: Postmarketing surveillance in Japan

We performed a postmarketing surveillance study to determine the efficacy and safety of the oral quinolone antibacterial agent garenoxacin (Geninax^® Tablets 200 mg) against atypical pneumonia.Between October 2009 and July 2011, patients with community-acquired pneumonia visited 26 facilities in Japan; we collected survey forms from 105 of these patients who were suspected of having atypical pneumonia based on the Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia in Adults. We examined the safety in 105 patients and the efficacy in 71 patients.1. The efficacy rates among patients suspected of having atypical pneumonia and those with a confirmed diagnosis of atypical pneumonia were 94.8% (55/58 patients) and 92.3% (12/13 patients), respectively. The efficacy rate was 4/4 for patients in whom Chlamydophila pneumoniae was detected (including 1 patient with a polymicrobial infection with another bacterial strain) and 90% (9/10 patients) for patients in whom Mycoplasma pneumoniae was detected (garenoxacin was ineffective in 1 of 2 patients with a polymicrobial infection with another bacterial strain).2. The incidence of adverse drug reactions (including abnormal laboratory tests) was 4.8% (5/105 patients). Among the adverse drug reactions, gastrointestinal disorders, infection and infestation, nervous system disorder, and skin and subcutaneous tissue disorder were observed in 2.9% of patients (3/105), 1.0% (1/105), 1.0% (1/105), and 1.0% (1/105), respectively.In conclusion, garenoxacin showed an efficacy rate of greater than 90% for suspected atypical pneumonia and confirmed atypical pneumonia. Garenoxacin is considered to be useful in daily practice.     

Post-marketing cohort study comparing the safety and efficacy of flunarizine and propranolol in the prophylaxis of migraine

A comparative post-marketing surveillance study of the safety and efficacy of flunarizine and propranolol in the treatment of migraine was carried out. General practitioners in Belgium and the Netherlands each recruited patients for whom they would prescribe one of the study medications in the normal course of their treatment and recorded all medical events on follow-up forms for up to 8 months. A total of 1601 migraine patients were enrolled; 838 in the flunarizine cohort and 763 in the propranolol cohort. Propranolol was somewhat better than flunarizine in reducing the severity of migraine attacks, although this may have been due to a selection bias. Discontinuations of therapy due to events considered likely to be treatment-related were mostly due to the recognized side effects of the two drugs. As regards the occurrence of depressions, a total of 58 patients had depressive events, 34 in the flunarizine cohort and 24 in the propranolol cohort. Whereas migraine itself appears to be associated with an increased risk of depression, the number of previous migraine treatments was shown to be an additional risk factor for the development of depression in patients receiving flunarizine as was a history of depression. Overall, there was no appreciable difference in the risk/benefit ratio between flunarizine and propranolol.     

Postmarketing surveillance study of nateglinide in Japan

Nateglinide is an oral antidiabetic medication that acts through rapid, short-term stimulation of insulin production. This study was undertaken to identify the incidence and nature of adverse effects of nateglinide and to assess its efficacy in clinical practice. Patients (n=3254) were recruited from 606 centers in Japan with a 12-week observation period. Pretreatment and posttreatment values were obtained for fasting blood glucose, postprandial blood glucose, hemoglobin A_1c (HbA_1c), triglycerides, cholesterol, and body mass index. All adverse events were reported, along with standard laboratory blood variables. The incidence of adverse events was 7.40%; hypoglycemia, including hypoglycemic symptoms, was reported as the most prevalent (1.62%). Adverse events were observed more frequently in patients with hepatic or renal dysfunction; no significant findings were noted in the remaining patient population. The efficacy rating determined by the treating physicians was 76.40%. HbA_1c decreased by 0.81% from 7.70±1.53% to 6.89±1.22%, postprandial glucose decreased by 54.05 mg/dL from 228.91±73.69 mg/dL to 174.86±62.86 mg/dL, and fasting glucose decreased by 23.73 mg/dL from 164.15±51.42 mg/dL to 140.43±42.63 mg/dL. These effects were most marked in patients who were previously medication naïve or who had been diagnosed with diabetes for a short period. Mean body mass index decreased, and nateglinide was equally effective in obese patients. Nateglinide showed good therapeutic effect when used as the first choice in patients with a short duration of diabetes, and in those with no history of previous treatment. Moreover, nateglinide seemed to be useful for the treatment of elderly patients and obese patients.     

Rotavirus vaccination in Japan: Efficacy and safety of vaccines,changes in genotype,and surveillance efforts

In Japan, a monovalent rotavirus vaccine (RV1) and a pentavalent rotavirus vaccine (RV5) were launched as voluntary vaccinations in November 2011 and July 2012, respectively. Rotavirus (RV) vaccine coverage in Japan increased from 30.0% in 2012 to 78.4% in 2019. The number of RV gastroenteritis hospitalizations decreased after 2014 in Japan, and is expected to decrease further following the introduction of RV vaccines into the national immunization program in October 2020. The incidence rates of intussusception (IS) among children aged <1 year were 102.8 and 94.0 per 100,000 person-years in the pre-vaccine (2007–2011) and post-vaccine (2012–September 2014) eras, respectively. IS incidence did not increase following RV vaccine introduction in Japan. The efficacy and safety of RV vaccination were both documented in Japan. To reduce the risk of IS following RV vaccination, it is important that children receive a first dose of RV vaccine at age <15 weeks, preferably at age 2 months. Some strains that have emerged since RV vaccine introduction, such as DS-1-like G1P[8], eG3, and G8P[8], have spread nationwide. These three emerging genotypes did not affect the severity of the RV infection. Continuous city-level surveillance, using analysis of all 11 RV genome segments, is necessary to elucidate the genetic characteristics of prevalent RV strains. These efforts would also clarify the influence of vaccination on genetic changes of RV strains and the emergence of new genotypes.     

Multicenter surveillance of adult atypical pneumonia in Japan: its clinical features,and efficacy and safety of clarithromycin

A prospective multicenter study involving 156 Japanese medical institutions was conducted to clarify the clinical features of adult atypical pneumonia and the efficacy and safety of clarithromycin. Atypical pneumonia was suspected in 730 patients according to the Japanese Respiratory Society’s Guidelines for the Management of Community-Acquired Pneumonia in Adults, and clarithromycin was administered. On the basis of bacteriological and serological tests, 465 patients were diagnosed with atypical pneumonia. Mycoplasma pneumonia was common among younger patients and chlamydia pneumonia among older patients. Underlying respiratory disease was uncommon among mycoplasma patients but prevalent among chlamydia patients. According to the severity classification given in the abovementioned guidelines, most mycoplasma patients had mild infection, whereas a high percentage of chlamydia patients had moderate infections. Body temperature was higher and coughing more severe in the mycoplasma patients than in the chlamydia patients. On the other hand, intergroup differences were not observed regarding extent of lung shadowing on plain radiographs, peripheral white blood cell count, or C-reactive protein (CRP). The effectiveness of clarithromycin was 96.8% in mycoplasma patients (153/158), 92.9% in chlamydia patients (78/84), and 96.0% in the group comprising all atypical pneumonia patients, including those with superinfection (288/300). The incidence of adverse drug reactions was 3.4% (24/698). Macrolide resistance in Mycoplasma pneumoniae has been reported in Japan, but the results of this surveillance study showed that clarithromycin is effective in treating adult atypical pneumonia.     

Enteric-Coated Aspirin Versus Other Antiplatelet Drugs in Acute Non-Cardioembolic Ischemic Stroke: Post-marketing Study in Japan

Introduction

Japanese guidelines recommend aspirin 160–300 mg/day, starting within 48 h, for patients with acute cerebral infarction. However, there are few reports evaluated in Japanese patients. Our objective was to examine the safety and efficacy of enteric-coated aspirin, compared with other oral antiplatelet drugs, in Japanese patients with acute ischemic stroke.

Methods

We performed a prospective, non-randomized, observational and multicenter study between June 2005 and December 2007. Patients with symptomatic acute ischemic stroke, including transient ischemic attack (TIA), who started enteric-coated aspirin or other antiplatelet drugs within 7 days of hospitalization were registered. Outcome measures evaluated within 3 months were incidence of cerebral and non-cerebral hemorrhagic events, recurrence of ischemic stroke or TIA, non-cerebral ischemic events and death from any cause.

Results

Overall, 2,548 and 830 patients treated with enteric-coated aspirin (100–300 mg/day) or other antiplatelet drugs, respectively, were registered; approximately 60% were male, mean age was 70 years, 85% had pre-existing cardiovascular disease or other complications. Enteric-coated aspirin of 100 mg was mainly prescribed, and only approximately half of the patients were started on it within 48 h after onset of ischemic stroke. Safety and efficacy population excluded patients without follow-up data were 2,521 in enteric-coated aspirin and 807 in other antiplatelets. Hemorrhagic events occurred in 46 (1.8%) in the enteric-coated aspirin group and in 13 (1.6%) in the other antiplatelet drugs group, there was not significant. Recurrent ischemic stroke or TIA occurred in 39 (1.5%) of the enteric-coated aspirin and in 18 (2.2%) of other antiplatelet drugs, and there were any-cause death in 16 (0.6%) and 8 (1.0%). Incidences were slightly lower in the enteric-coated aspirin group compared with the other antiplatelet drugs group, but not statistically significant.

Conclusion

It seems that these results showed the safety and efficacy of the enteric-coated aspirin in acute stroke care in Japanese patients. Incidence of hemorrhagic events was comparable between the enteric-coated aspirin group and the other antiplatelet drugs group.     

奈诺沙星与左氧氟沙星治疗社区获得性肺炎的疗效及安全性比较

奈诺沙星是一种无氟喹诺酮类,对包括青霉素耐药和其他喹诺酮类药物耐药肺炎链球菌、甲氧西林耐药和万古霉素耐药金葡菌在内的社区获得性肺炎(CAP)病原菌有良好的体内、体外抗菌活性。本研究将265例轻至中度CAP患者随机分组,接受口服奈诺沙星(750mg或500mg)或左氧氟