Overview of Semaglutide Tablets Safety Data

Overview of Semaglutide Tablets Safety Data

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Overview of Semaglutide Tablets Safety Data

Editor’s Note

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have been used for nearly 20 years in the management of blood glucose in patients with type 2 diabetes (T2DM) since their launch. With the increasing evidence from research, the efficacy of some GLP-1RAs in effective glucose lowering, multiple metabolic improvements, and cardiovascular benefits has been widely recognized. Their recommended status in authoritative guidelines both domestically and internationally has been continuously elevated, making them a priority recommendation in multiple clinical application pathways, benefiting an increasingly broad patient population. Semaglutide tablets, as the only oral GLP-1RA currently available globally, have promoted the early and widespread application of GLP-1RAs in T2DM populations. Meanwhile, the drug safety and patient tolerance of GLP-1RAs have also attracted the attention of many clinical doctors and patients. So, how safe are semaglutide tablets, which will soon be launched in China? This article invites Professor Chen Lulu from Huazhong University of Science and Technology Tongji Medical College Union Hospital to provide a detailed interpretation of the safety data from the phase 3 clinical studies of semaglutide tablets—based on the safety data summary analysis from the PIONEER series studies.

1

Introduction to Semaglutide Tablets

Semaglutide tablets are currently the only approved oral medication among GLP-1RAs. By co-formulating with the permeation enhancer N-(8-[2-hydroxybenzoyl]-amino)caprylic acid (SNAC), the semaglutide molecule can overcome the gastric mucosal barrier and be absorbed into the bloodstream, significantly increasing the oral bioavailability of semaglutide. Its excellent glucose-lowering efficacy and multiple metabolic benefits have been widely confirmed in a series of phase 3 clinical studies (PIONEER series studies). In head-to-head studies with other novel oral hypoglycemic agents such as sodium-glucose co-transporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i), semaglutide tablets have shown a greater reduction in glycated hemoglobin (HbA1c) levels and superior overall metabolic benefits, including weight loss. Since 2019, semaglutide tablets have been launched in more than 40 countries and regions worldwide, and will soon enter China to assist a large number of Chinese T2DM patients in managing their blood glucose.
Currently, among the 10 published PIONEER studies, one is a cardiovascular outcome trial (CVOT)—PIONEER 6, while the other 9 studies explored the efficacy and safety of semaglutide tablets in the overall management of T2DM compared to control groups (including placebo and active drugs like sitagliptin, empagliflozin, and liraglutide). In the 9 PIONEER studies (excluding PIONEER 6), a total of 4116 patients were exposed to semaglutide tablets (including all doses of 3mg, 7mg, and 14mg), while 2236 patients used placebo or active control drugs, with similar baseline distributions between the two groups (Table 1).
Table 1 Summary Analysis of Baseline Characteristics in PIONEER Series Studies

Overview of Semaglutide Tablets Safety Data

Note: Data are from the summary analysis of PIONEER 1-5, 7-10, with the control group including active control drugs and placebo.

2

Overall Tolerance of Patients is Good,

Gastrointestinal Adverse Events are Most Common

Overall, the proportion of patients experiencing serious adverse events with semaglutide tablets is similar to that of the control group (8.6% vs 9.0%), and most adverse events are mild to moderate (severe adverse events 6.6% vs 6.8%). The proportion of patients discontinuing treatment due to adverse events is slightly higher than that of the control group (8.7% vs 4.2%), mainly due to a higher proportion of patients discontinuing treatment due to gastrointestinal adverse events (5.9% vs 1.8%) (Figure 1).

Overview of Semaglutide Tablets Safety Data

Figure 1 Summary Analysis of Overall Adverse Events in PIONEER Series Studies
Note: Data are from the summary analysis of PIONEER 1-5, 7-10, with the control group including active control drugs and placebo; SAE, serious adverse events; AE, adverse events; GIAE, gastrointestinal adverse events.
Consistent with injected GLP-1RAs, gastrointestinal adverse events are the most common adverse events associated with semaglutide tablets, but generally of mild severity (the incidence of severe events is only 1.6%). Among these, nausea (15.4%) and diarrhea (10.1%) are relatively common, but usually occur during the initial dose escalation phase of treatment and gradually diminish over time. Additionally, as the drug exposure concentration of semaglutide tablets increases, there is a trend of increased incidence of nausea. (Figure 2).

Overview of Semaglutide Tablets Safety Data

Figure 2 Incidence of Nausea Among Patients in the PIONEER Series

Note: The left figure shows data that only includes placebo-controlled trials in the PIONEER series (PIONEER 1, 4, 5, 7) and demonstrates the severity and patient proportion of nausea among different dose groups of semaglutide tablets and the placebo group over time; the right figure includes data from PIONEER 1-3, 5, 8, 9, showing the distribution range of drug concentrations for different doses of semaglutide tablets, and the relationship between the proportion of patients experiencing nausea and drug concentration.

To improve adherence to semaglutide tablets, it is necessary to refine patient education and management:
  • Inform patients that gastrointestinal reactions are the most common adverse reactions, such as nausea and diarrhea.
  • Help patients distinguish between increased satiety (one of the drug’s effects) and feelings of discomfort/nausea.
  • Most gastrointestinal reactions are mild to moderate and rarely lead to treatment discontinuation.
  • Gastrointestinal reactions usually occur early in treatment and tend to lessen over time.
  • Start with a small dose and gradually increase to reduce gastrointestinal reactions.
  • Avoid discontinuation of treatment as much as possible, based on what the patient can tolerate.

3

Key Areas of Focus

3.1 Semaglutide Tablets Are Safe for Glycemic Control with Low Risk of Hypoglycemia

The risk of hypoglycemia is a key event that needs attention for any hypoglycemic medication. Studies have shown that severe hypoglycemic events can significantly increase the risk of cardiovascular death. Authoritative guidelines both domestically and internationally emphasize the need to balance hypoglycemia risk while controlling blood glucose. GLP-1RA drugs stimulate insulin secretion in a glucose concentration-dependent manner, exhibiting a “smart glucose-lowering” safety profile that effectively lowers blood sugar without increasing the risk of hypoglycemia.
In the summary analysis of the PIONEER series studies, the incidence of severe hypoglycemia with semaglutide tablets was low and similar to that of the control group (0.2% vs 0.1%). However, when background medications included insulin, there was an increasing trend in the incidence of severe hypoglycemia in both groups (1.1% vs. 0.4%) (Figure 3). In the pre-marketing cardiovascular outcome trial PIONEER 6, a similar incidence of severe hypoglycemia was observed for semaglutide tablets compared to placebo (1.4% vs 0.8%), all occurring in patients using sulfonylureas or insulin as background medications.

Overview of Semaglutide Tablets Safety Data

Figure 3 Incidence of Severe Hypoglycemia Among Patients in the PIONEER Series
Note: Data are from the summary analysis of PIONEER 1-5, 7-10, with the control group including active control drugs and placebo; severe hypoglycemia (as defined by ADA): refers to hypoglycemic events requiring third-party assistance; SU, sulfonylureas; OAD, oral hypoglycemic agents; MET, metformin.
Based on the safety data regarding hypoglycemia for semaglutide tablets, the European Medicines Agency (EMA) recommends in its product information:
  • Self-monitoring of blood glucose is not required during dose adjustments of semaglutide tablets.
  • When semaglutide tablets are used in combination with sulfonylureas or insulin, consideration should be given to reducing the dose of sulfonylureas or insulin to lower the risk of hypoglycemia.
  • Self-monitoring of blood glucose is necessary when adjusting doses of sulfonylureas and insulin, especially when initiating semaglutide tablets and reducing insulin dosage.

3.2 No Increased Risk of Malignant Tumors with Semaglutide Tablets

Thyroid safety issues are a key area of concern for GLP-1RA medications, particularly the risk of medullary thyroid carcinoma. In the summary analysis of PIONEER data, very few patients developed thyroid tumors (2 cases in the semaglutide group and 1 case in the control group), and no cases of medullary thyroid carcinoma were found. Only in the PIONEER 6 study was one case of medullary thyroid carcinoma identified in the semaglutide group, but this patient had pre-existing thyroid nodules and elevated calcitonin levels at baseline.
Overall, the proportion of patients with malignant tumors in the semaglutide group is comparable to that in the control group (Figure 4), and when considering the incidence of tumors in various organs during the trial, the semaglutide group did not show a higher risk of tumor occurrence. However, the duration of phase 3 clinical trials is relatively short, and given the natural course of tumors, more post-marketing monitoring data are still needed to evaluate the long-term safety of GLP-1RA medications.

Overview of Semaglutide Tablets Safety Data

Figure 4 Incidence of Malignant Tumors in the PIONEER Series Studies
Note: The summary of PIONEER studies includes data from PIONEER 1-5, 7-10, with the control group including active control drugs and placebo; PIONEER 6 control group is placebo.
The FDA product information emphasizes:
  • Semaglutide tablets are contraindicated in patients with a history or family history of medullary thyroid carcinoma and in patients with type 2 multiple endocrine neoplasia syndrome.
  • Patients should be informed of the potential risk of medullary thyroid carcinoma and the symptoms of thyroid tumors.

3.3 No Increased Risk of Pancreatitis with Semaglutide Tablets

Currently, there is no evidence indicating a correlation between the use of GLP-1RA and acute pancreatitis. Given prior reports of acute pancreatitis following GLP-1RA use, pancreatitis remains one of the most scrutinized safety areas for GLP-1RA. In the summary analysis of PIONEER and the placebo-controlled cardiovascular outcome trial PIONEER 6, no increased incidence of acute pancreatitis was observed in the semaglutide group (Figure 5).

Overview of Semaglutide Tablets Safety Data

Figure 5 Incidence of Acute Pancreatitis in the PIONEER Series Studies
Note: The summary of PIONEER studies includes data from PIONEER 1-5, 7-10, with the control group including active control drugs and placebo; PIONEER 6 control group is placebo.
Based on prior medication experience and safety data, the FDA product information provides the following recommendations:
  • Patients with a history of pancreatitis should use semaglutide tablets with caution.
  • If pancreatitis is suspected, semaglutide tablets should be discontinued; once pancreatitis is confirmed, semaglutide tablets should not be used for treatment.
  • In clinical practice, patients should be informed of the characteristic symptoms of acute pancreatitis.

3.4 No Increased Risk of Gallbladder Disease with Semaglutide Tablets

Clinical trials of GLP-1RA have reported an increased incidence of acute gallbladder events (such as gallstones or cholecystitis) compared to control groups, thus safety issues related to gallbladder medications have also received attention. Studies have shown that rapid weight loss is a risk factor for cholecystitis and gallstones. GLP-1RA medications are known for their weight loss effects, although a direct link cannot be established, it cannot be ruled out that this effect is related. In the summary analysis of the phase 3 clinical studies of semaglutide tablets, the proportion of patients experiencing gallbladder-related adverse events (including gallstones, cholecystitis, hyperbilirubinemia, biliary colic, etc.) was 1.2%, similar to the control group (1.1%). Among these, gallstones were the most common (0.7% vs 0.8%) (Figure 6). In the PIONEER 6 study, semaglutide tablets did not increase the risk of gallstones compared to placebo (0.1% vs 0.3%).

Overview of Semaglutide Tablets Safety Data

Figure 6 Incidence of Gallstones in the PIONEER Series Studies
Note: The summary of PIONEER studies includes data from PIONEER 1-5, 7-10, with the control group including active control drugs and placebo; PIONEER 6 control group is placebo.
The current FDA product information recommends:
  • If gallstones are suspected, gallbladder examination and appropriate clinical follow-up are required.
  • Prior to medication, enhance communication and guidance with patients, informing them of the potential risks of gallstones or cholecystitis, and guiding them to seek timely medical attention in case of suspected gallstones or cholecystitis.

3.5 Semaglutide Tablets Have Confirmed Cardiovascular Safety

Cardiovascular adverse events are significant comorbidities and causes of death in T2DM patients. The FDA requires all newly launched hypoglycemic drugs to undergo cardiovascular risk assessments and must demonstrate good cardiovascular safety. The pre-marketing cardiovascular outcome trial PIONEER 6 has verified the cardiovascular safety of semaglutide tablets, showing that semaglutide tablets do not increase the risk of major adverse cardiovascular events (MACE) compared to placebo (Figure 7). Data from the summary analysis of PIONEER also supports this conclusion, with a similar proportion of patients experiencing MACE in the semaglutide group compared to the control group (1.0% vs. 1.2%).

Overview of Semaglutide Tablets Safety Data

Figure 7 Proportion of Patients with Major Adverse Cardiovascular Events in PIONEER 6
Note: MACE, major adverse cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.
To further explore whether semaglutide tablets have cardiovascular protective effects, a large efficacy-designed cardiovascular outcome study—SOUL study (NCT03914326)—was initiated in 2019, enrolling 9650 T2DM patients with atherosclerotic cardiovascular disease (ASCVD) or high-risk factors for ASCVD, randomly assigned to either 14mg semaglutide tablets or placebo, with a follow-up period of up to 5 years. This study will provide more comprehensive evidence support for the cardiovascular benefits of semaglutide tablets.

3.6 No Increased Risk of Diabetic Retinopathy with Semaglutide Tablets (DR) Safety Signals

Multiple studies have found that rapid improvement in blood glucose may be associated with transient worsening of DR. The safety issue of whether the effective glucose-lowering of GLP-1RAs may lead to DR has also attracted the attention of clinical experts. Currently, there is no definitive conclusion regarding the impact of GLP-1RAs on DR. According to the summary analysis of PIONEER data, the proportion of patients experiencing DR is similar between the semaglutide group and the control group (3.3% vs 3.0%) (Figure 8 left). In PIONEER 6, the cumulative incidence of DR complications was similar between the semaglutide and placebo groups, with very few severe events occurring. (Figure 8 right).

Overview of Semaglutide Tablets Safety Data

Figure 8 Proportion of Patients with DR in the PIONEER Series Studies
Note: The summary of PIONEER studies includes data from PIONEER 1-5, 7-10, with the control group including active control drugs and placebo; DR, diabetic retinopathy.
The FDA product information provides the following recommendations:
  • Patients with a history of DR should monitor the progression of DR during treatment with semaglutide tablets.
  • If patients experience changes in vision during treatment with semaglutide tablets, they should seek medical attention promptly.

3.7 No Increased Risk of Renal Adverse Events with Semaglutide Tablets

When selecting hypoglycemic medications, it is usually necessary to fully consider the patient’s renal function and adjust the medication dosage based on eGFR. Early pharmacokinetic studies of semaglutide tablets indicated that there were no significant differences in the half-life of semaglutide tablets among patients with varying degrees of renal impairment (152~165h), and the degree of renal impairment did not significantly affect the blood concentration of semaglutide tablets. Therefore, patients with mild to moderate renal impairment do not need dosage adjustments when using semaglutide tablets. PIONEER 5 validated the efficacy and safety of semaglutide tablets in T2DM patients with moderate renal impairment, and the average eGFR level of patients remained stable during the trial.
In the summary analysis of the PIONEER series and the renal overall safety of PIONEER 6, the incidence of renal adverse events was similar between the semaglutide group and the control group (Figure 9). However, it should be noted that there have been reports of acute kidney injury or chronic renal function deterioration in patients using GLP-1RA post-marketing, with most events reported occurring in patients with nausea, vomiting, diarrhea, or dehydration. In the PIONEER series studies, the proportion of patients experiencing acute kidney injury (AKI) was similar between the semaglutide and control groups, and both were at a low level (Figure 9), with some AKI occurrences related to gastrointestinal adverse events and insufficient fluid intake. This further emphasizes the importance of patient management and education.

Overview of Semaglutide Tablets Safety Data

Figure 9 Incidence of Renal Adverse Events in the PIONEER Summary Analysis

Note: The summary of PIONEER studies includes data from PIONEER 1-5, 7-10, with the control group including active control drugs and placebo; PIONEER 6 control group is placebo.

EMA and FDA Recommendations for Semaglutide Tablets:
  • No dosage adjustment is needed for patients with mild to moderate renal impairment; currently, experience in using semaglutide tablets in patients with severe renal impairment is limited.
  • Semaglutide tablets are not recommended for use in patients with end-stage renal disease.
  • Patients experiencing severe gastrointestinal adverse reactions during treatment should have their renal function monitored.

Conclusion

As the clinical application of GLP-1RAs becomes increasingly widespread, the safety and patient tolerance of these medications have attracted significant attention. Semaglutide tablets represent a new formulation of GLP-1RA, increasing treatment options for T2DM patients while further expanding the application range of GLP-1RAs. The PIONEER series studies have confirmed that semaglutide tablets exhibit potent glucose-lowering effects and multiple metabolic benefits. This article analyzes the safety areas of various GLP-1RA medications based on the summary data from the PIONEER series studies. Overall, semaglutide tablets have good safety profiles, with gastrointestinal adverse events being common but mostly tolerable and diminishing over time; the drug has a low risk of hypoglycemia and has not shown an increasing trend of safety risks regarding pancreatitis, gallbladder diseases, or diabetic retinopathy. It is also emphasized that patient health education and management play a positive role in reducing adverse drug reactions and improving treatment adherence.
This article aims to help clinical doctors gain a comprehensive understanding of the safety data for this new oral hypoglycemic drug, providing a basis for the future clinical practice of semaglutide tablets in managing T2DM in China. However, the duration of phase 3 clinical trials is relatively short, and the safety assessment of the drug still requires long-term validation. With the further disclosure of long-term clinical trial results and the continuous accumulation of real-world practice experience, it is believed that clinical doctors will gain a more comprehensive understanding of the safety of semaglutide tablets.
Expert Profile

Overview of Semaglutide Tablets Safety Data

Chen Lulu

  • Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

  • Associate Professor, Chief Physician, Doctor of Medicine, Doctoral Supervisor, Expert enjoying special government allowances from the State Council.

  • Vice Chairman of the 10th Committee of the Endocrinology Society of the Chinese Medical Association;

  • Vice Chairman of the Diabetes Professional Committee of the Chinese Women Physicians Association;

  • First batch of specially invited experts from the Center for Drug Evaluation of the National Medical Products Administration;

  • Former Chairman of the Hubei Diabetes Society;

  • Chairman of the 4th and 5th Hubei Endocrinology Society;

  • Vice Chairman of the Cardiovascular Metabolic Disease Physician Committee of the Hubei Preventive Medicine Association;

  • Director of the Hubei Clinical Medical Research Center for Diabetes and Metabolic Diseases;

  • Director of the Quality Control Center for Endocrinology and Diabetes in Hubei Province.

  • Involved in key projects of the National Key Research and Development Program, multiple National Natural Science Foundation projects, the 11th Five-Year Plan Support Project, and major projects of the Hubei Provincial Science and Technology Department. Published 411 articles and professional papers in domestic and international academic journals, including 108 SCI articles. Awarded first and second prizes for scientific and technological progress in Hubei Province and the first prize for the Chinese Medical Science and Technology Award. Recognized as one of the top ten medical influencers in China in 2021.

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[2]. Davies MJ, et al. Diabetes Care. 2022 Sep 23:dci220034.
[3]. Aroda VR, Erhan U, Jelnes P, et al. Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes[J]. Diabetes Obes Metab, 2023,25(5):1385-1397. doi:10.1111/dom.14990.
[4]. Buckley ST, Bækdal TA, Vegge A, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist[J]. Sci Transl Med. 2018 Nov 14;10(467):eaar7047. doi: 10.1126/scitranslmed.aar7047.
[5]. Rodbard HW, Rosenstock J, Canani LH, et al. Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial[J]. Diabetes Care, 2019,42(12):2272-2281. doi:10.2337/dc19-0883
[6]. Rosenstock J, Allison D, Birkenfeld AL, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the PIONEER 3 randomized clinical trial[J]. JAMA, 2019,321(15):1466-1480. doi:10.1001/jama.2019.2942
[7]. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes[J]. N Engl J Med, 2019,381(9):841-851. doi:10.1056/NEJMoa1901118.
[8]. Ji Linong, Zou Dajin, Hong Tianpei, et al. Expert Guidance on Clinical Application of GLP-1 Receptor Agonists[J]. Chinese Journal of Diabetes, 2018, 26(5): 353-361.
[9]. Standl E, Stevens SR, Lokhnygina Y, et al. Confirming the Bidirectional Nature of the Association Between Severe Hypoglycemic and Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL[J]. Diabetes Care. 2020 Mar;43(3):643-652. doi: 10.2337/dc19-1079.
[10]. Semaglutide Tablets European Product Information https://www.ema.europa.eu/en/documents/product-information/rybelsus-epar-product-information_en.pdf.
[11]. Semaglutide Tablets US Product Information https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213051s012lbl.pdf.
[12]. He L, Wang J, Ping F, et al. Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials[J]. JAMA Intern Med. 2022 May 1;182(5):513-519. doi: 10.1001/jamainternmed.2022.0338.
[13]. Monami M, Nreu B, Scatena A, et al. Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized controlled trials[J]. Diabetes Obes Metab. 2017 Sep;19(9):1233-1241. doi: 10.1111/dom.12926.
[14]. Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control [EB/OL].(2020).www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
[15]. Nauck MA, Quast DR. Cardiovascular Safety and Benefits of Semaglutide in Patients With Type 2 Diabetes: Findings From SUSTAIN 6 and PIONEER 6[J]. Front Endocrinol (Lausanne). 2021 Mar 29;12:645566. doi: 10.3389/fendo.2021.645566.
[16]. Brinchmann-Hansen O, Dahl-Jorgensen K, Hanssen KF, Sandvik L. Effects of intensified insulin treatment on various lesions of diabetic retinopathy. Am J Ophthalmol. 1985; 100: 644-653.
[17]. The ROC Collaborative Study Group. Blood glucose control and the evolution of diabetic retinopathy and albuminuria. A preliminary multicenter trial. N Engl J Med. 1984; 311: 365-372.
[18]. Chinese Medical Association Diabetes Society Microvascular Complications Group. Guidelines for the Prevention and Treatment of Diabetic Kidney Disease in China (2021 Edition) [J]. Chinese Journal of Diabetes, 2021, 13(8): 762-784.
[19]. Chinese Medical Association Nephrology Society Expert Group. Clinical Diagnosis and Treatment Guidelines for Diabetic Kidney Disease in China [J]. Chinese Journal of Diabetes, 2021, 37(3): 255-303.
[20]. Granhall C, Søndergaard FL, Thomsen M, et al. Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment[J]. Clin Pharmacokinet. 2018 Dec;57(12):1571-1580. doi: 10.1007/s40262-018-0649-2.
[21]. Mosenzon O, Blicher TM, Rosenlund S, et al. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial[J]. Lancet Diabetes Endocrinol, 2019,7(7):515-527. doi:10.1016/S2213-8587(19)30192-5.

Overview of Semaglutide Tablets Safety Data

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Overview of Semaglutide Tablets Safety Data

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