A laboratory data-based evaluation of the efficacy and safety of generic pravastatin sodium for long-term use

Increasing the use of generic instead of branded drugs is desirable since it contributes to reducing healthcare spending [1]. Although the generic drugs’ penetration rates are approximately 50 % or more in Europe and the United States, according to an aggregated value based on a drug price survey conducted in September 2013, they are 46.9 % in Japan, and are currently still low [2, 3]. To address this situation, the Japanese Ministry of Health, Labour and Welfare has set a goal to increase the volume share of generic drugs to 60 % or more by the fiscal year of 2018. Promotion of the use of generics also plays a large role in the medical economy [4].

One of the reasons for the persistently low penetration rate of generic drugs is the distrust of doctors and patients because less information on their efficacy and safety is available than that for branded drugs [5]. To address this issue, it is important not only to ensure the biological and therapeutic equivalence of generic drugs to those of branded drugs, but also to clinically assess their efficacy and safety.

When we switched from branded to generic pravastatin sodium tablets at our hospital, we assessed the clinical efficacy and safety of the generic version on the basis of laboratory data and reported our findings [6]. In this study, which included all 1337 patients who switched to the generic pravastatin sodium tablet Maibastan® (Towa Pharmaceutical, Co., Ltd.), we demonstrated that Maibastan®’s clinical efficacy and safety were comparable to those of the branded Mevalotin® tablet (Daiichi Sankyo Co., Ltd.). However, since the study period was 6 months and the long-term use of Mevalotin® was defined as 15 months or longer [6], the impact of Maibastan®’s long-term use on clinical efficacy and safety remains unknown. Moreover, although several clinical studies have compared and analyzed the efficacy and safety of branded and generic drugs in patients switching from branded to generic drugs, only few have investigated the clinical efficacy and safety of the long-term use of the latter [7–9]. Thus, in the present study, the duration of long-term use was defined as 15 months or longer [10], and the study period was extended to last from January 1, 2008 to December 31, 2011. All 1337 patients who had switched to Maibastan® in the previous study were followed up, and a retrospective observational study using information from electronic medical records to assess Maibastan®’s long-term use clinical efficacy and safety was conducted.

Among the 39 patients in the treatment discontinuation group (long-term), the reasons for discontinuation were not clearly indicated in the medical records of 28 patients. In five patients, treatment was discontinued because of transfer to another hospital and because of death, pregnancy, poor nutritional status, and advanced age preventing chronic treatment in 3, 1, 1, and 1 patient(s), respectively.

Among the 278 patients in the treatment discontinuation group (short-term), the reasons for discontinuation were not clearly indicated in the medical records of 141 patients. In 62 patients, treatment was discontinued because of transfer to another hospital, and in 33, 21, 13, 3, 3, and 2 patients, because of death, adverse reactions, decreased LDL-C levels, poor nutritional status, patient’s own request, and old age preventing chronic treatment, respectively. Among the 21 patients who discontinued treatment because of adverse reactions, eight patients presented symptoms suggestive of rhabdomyolysis, such as increased CPK levels and myalgia.

Among the 329 patients in the drug-change group, the reasons for drug change were not clearly indicated in the medical records of 187 patients. Maibastan® was replaced by other drugs because of poor LDL-C control in 116 patients (Crestor® [AstraZeneca, Inc.; 61 patients], Lipitor® [Astellas Pharma, Inc.; 54 patients], and Bezatol® [Kissei Pharmaceutical Co., Ltd.; 1 patient]) and because of poor TG control in 9 patients (Crestor®, Lipitor®, Bezatol®, and Lipidil® [Kaken Pharmaceutical Co., Ltd.; 2 patients each] and Zetia® [Bayer AG; 1 patient]). Moreover, 1 patient switched from Maibastan® to another drug (Bezatol®) because of favorable LDL-C control. Adverse reactions caused all 16 patients to switch from the generic drug to other drugs (Lipitor® tablet in 9 patients, Crestor® and Zetia® tablet in 3 patients each, and Epadel® capsule [Mochida Pharmaceutical Co., Ltd.] in 1 patient). Nine of the patients presented symptoms suggestive of rhabdomyolysis, such as increased CPK levels, myalgia, and weakness.

Among the 98 patients in the dose-adjustment group, the reasons for drug change were not clearly indicated in the medical records of 33 patients. In 37 patients, the doses of Maibastan® tablet were reduced because of favorable LDL-C control, and in 27 and 1 patient(s), because of poor LDL-C and TG control, respectively.

Among the 37 patients in the concomitant drug-change group, the reasons for drug change were not clearly indicated in the medical records of 17 patients. In 11 patients, other drugs were added as treatment because of poor LDL-C control (Zetia® tablet in 10 patients and Bezatol® tablet in 1 patient) and poor TG control in 9 patients (Zetia® and Bezatol® tablet in 3 patients each, Lipidil® tablet in 2 patients, and Perycit® tablet [Sanwa Kagaku Kenkyusho Co., Ltd.] in 1 patient).

Moreover, CTCAE grade II or higher adverse reactions were observed in 2 patients with increased CPK levels (grade II and IV) and in 1 patient each with increased γ-GTP levels, decreased Hb levels, and thrombocytopenia (all were grade II). The adverse reactions reported by 24 patients were myalgia in 7, rash in 6, discomfort in 3, and myospasm in 2 patients, as well as arrhythmia, numbness, malaise, nausea, weakness, and vertigo in 1 patient each. Of these reported adverse reactions, muscle-associated adverse reactions suggestive of rhabdomyolysis (increased CPK levels, myalgia, myospasm, numbness, malaise, and weakness) accounted for a large proportion of the patients (21 out of 37).

Case 1 is a 48-year-old man treated for dyslipidemia on an outpatient basis. Ten months after switching to Maibastan® tablet, he complained of discomfort, and drug treatment was discontinued. The patient’s discomfort was related to the use of Maibastan® tablet together with 2 drugs prescribed for sinusitis at another hospital (unspecified). The other concomitant drugs used were Bayaspirin® tablet (Bayer AG), Juvela® capsule (Eisai Co., Ltd.), and Foliamin® tablet (Takeda Pharmaceutical Co., Ltd.). Discontinuation of all drugs relieved the patient’s discomfort.

Case 2 is a 76-year-old man treated for chronic renal failure, renal anemia, hypertension, prostatomegaly, and dyslipidemia on an outpatient basis. Two months after switching to Maibastan® tablet, he complained of discomfort, and drug treatment was discontinued. Because of discomfort, the patient discontinued the use of Urief® (Daiichi Sankyo Co. Ltd.), Maibastan®, Tenormin® (AstraZeneca, Inc.), and Myslee® tablet (AstraZeneca, Inc.) at his own discretion. The patient’s discomfort was subsequently relieved. The use of the other concomitant drugs, Adalat® (Bayer AG) and Blopress® tablet (Takeda Pharmaceutical Co., Ltd.), was not discontinued.

Case 3 is an 88-year-old woman treated for hypothyroidism and dyslipidemia on an outpatient basis. Two months after switching to Maibastan® tablet, she complained of discomfort, and drug treatment was discontinued. Because of discomfort, the patient discontinued Maibastan® and Hachimi-jio-gan® extract tablet (Kracie Pharma, Ltd.) at her own discretion. The patient’s discomfort was subsequently relieved. The use of the other concomitant drug, Thyradin-S® tablet (Takeda Pharmaceutical Co. Ltd.), was not discontinued.

Efficacy and safety assessment based on laboratory data included those of the patients in the long-term use group, which consisted of 556 patients in the long-term continued use and 39 patients in the treatment discontinuation (long-term) group. Regarding the efficacy in the long-term continued use group, no statistically significant difference was observed between the first TC, TG, HDL-C, and LDL-C levels measured during the short-term use of Maibastan® tablets and those of the last measured during the long-term treatment period. Furthermore, no significant difference between these parameters was observed in the treatment discontinuation group (long-term). Thus, it was assumed that the effects of the long-term use of Maibastan® tablets were similar to those of Mevalotin® tablets.

Similarly, regarding the safety assessment in the long-term continued use group, no statistically significant difference was observed between the first AST, ALT, CPK, γ-GTP, ALP, LDH, T-Bil, BUN, Scr, and HbA1c levels measured during the short-term use of Maibastan® tablet period and those of the last measurement during the long-term treatment period, except for the ALT levels. While the ALT levels were significantly lower in the Maibastan® tablet long-term use group than those in the short-term use group, the levels did not fluctuate throughout the long-term treatment period. A recent report from the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study indicated that the use of statins in patients with a fatty liver improved liver function and reduced cardiovascular events [11]. As for the reason for the decreased ALT levels, the report also suggested that the inhibitory action of Maibastan® against hepatic 3-methylglutaryl coenzyme A (HMG-CoA) reductase reduced stress, such as a fatty liver, affecting liver function. A similar comparison of the laboratory parameter values in the treatment discontinuation group showed no significant differences.

For the safety assessment, review of the patients’ medical records identified the reasons underlying all cases of drug discontinuation and change during the current study period. Detailed review of the medical records containing no documented reasons revealed the absence of patients’ complaints about symptoms suggestive of adverse reactions, abnormal laboratory data during treatment, or adverse events, such as death.

Next, to investigate the safety of the long-term use of Maibastan® tablets, the medical records of patients who had died or had adverse reactions were reviewed in detail. Among all the 36 patients who had died, drug discontinuation and change were suspected to be caused by primary diseases, and it was assumed that there was no causal relationship with the oral administration of Maibastan® tablets. In the drug discontinuation and change due to adverse reactions cases, Maibastan® tablet was considered responsible for each adverse reaction. Indeed, 21 out of the 37 cases showed muscle-associated symptoms suggestive of rhabdomyolysis (increased CPK levels, myalgia, myospasm, numbness, malaise, and weakness). However, these findings were derived from pravastatin sodium preparations and may be considered Maibastan® tablet-unrelated adverse reactions. Moreover, the adverse reactions observed in 12 out of the 37 cases, which included rash, increased ALP and γ-GTP levels, nausea, hepatopathy, thrombocytopenia, decreased Hb levels, and vertigo, were also reported for the branded drug (Mevalotin®), and no apparent increase in their incidence was observed. Thus, these adverse reactions may also be considered Maibastan® tablet-unrelated. Because discomfort (case 1, 2, and 3) and arrhythmia (case 4), which were observed in the remaining 4 cases, had not been reported in the adverse reaction reports for the branded drug, we investigated whether these adverse reactions were specific to Maibastan® tablet treatment. Although discomfort was relieved in these 3 cases(case 1, 2, and 3) after discontinuation of Maibastan® tablet, this adverse reaction may not be specific to the tablet: the patients were taking several oral drugs and had comorbidities associated with poor physical conditions, such as sinusitis, renal anemia, and hypothyroidism. Although the symptom(case 4) was relieved after discontinuation of Maibastan® tablet only, it has been reported that arrhythmic symptoms, such as extrasystole, are detected in approximately 3.8 % of healthy people, and that the incidence of such symptoms is higher in patients with hypertension [12, 13]. Because the patient of case 4 had concomitant hypertension, it cannot be ruled out that the racing pulse she experienced was caused by transient extrasystole. Thus, this symptom may not be a Maibastan® tablet-specific adverse reaction. According to the findings described above, it is assumed that Maibastan® tablet may be safely used for long-term treatment.

We previously conducted questionnaire surveys on generic drugs among doctors, nurses, and pharmacists at our hospital and found that several healthcare professionals had concerns about the limited amount of information on clinical efficacy and adverse reactions [14, 15]. Although several studies have examined the efficacy and safety of generic drugs, the number of studies focusing on individual drugs and the amount of information provided by such studies has not been sufficient to eliminate this concern. Some studies have also assessed the efficacy and safety of generic pravastatin sodium tablets. However, in several of these studies, less than 100 cases were evaluated, and the duration of generic drug treatment lasted for 3 months or less; even the longest duration lasted 6 months at most [16–19]. Drugs for the treatment of chronic diseases are often orally administered for many years. Especially, for dyslipidemia, strict long-term lipid control is necessary for the primary and secondary prevention of cardiovascular events. Thus, studies on the efficacy and safety of long-term drug use are highly useful information sources. The present study provides results on the efficacy and safety of a generic drug based on the assessment of a sufficient number of cases and sufficient treatment duration. The proliferation of generic drugs is highly desired to reduce healthcare spending. However, the major future tasks are not only to ensure their bioequivalence with branded drugs, but also to increase data provision on generic drug efficacy and safety by conducting clinical studies. In these tasks, pharmacists are essential since they are drug specialists. Therefore, pharmacists should be actively involved through pharmacist-led clinical assessments of generic drugs. The present study may have large clinical significance for the efficacy and safety assessment of the long-term use of generic drugs.

This study shows that the long-term use of generic pravastatin sodium is effective and safe, and may help dispel the concerns about generic drugs.