英文药名：Jentadueto(linagliptin and metformin hydrochloride)tablets

中文药名：利拉利汀/盐酸二甲双复方片剂

生产厂家：勃林格殷格翰/礼来
药品介绍
Jentadueto®（linagliptin的和盐酸二甲双胍片）-新型糖尿病复合制剂
2012年5月25日，勃林格殷格翰（Boehringer Ingelheim）和礼来（Eli Lilly）的新型糖尿病复合制剂Jentadueto（利拉利汀/盐酸二甲双胍）已收到欧盟人用医药产品委员会（CHMP）建议批准的积极意见。若最终获得了欧洲药品管理局（EMA）的批准，Jentadueto（利拉利汀/盐酸二甲双胍）将为那些需要改善血糖控制的2型糖尿病成人患者提供一种新的、日服2次的单一片剂治疗药物。CHMP已建议批准将Jentadueto和饮食及运动结合，来改善2型糖尿病成人患者的血糖控制。
在临床试验中，Jentadueto（利拉利汀/盐酸二甲双胍）已被证明能够使患者受益。经过安慰剂校正的糖化血红蛋白平均降低水平（placebo-corrected mean reductions in haemoglobin A1c，HbA1c或A1C）具有统计学意义。每日口服2次2.5mg利拉利汀/1000mg盐酸二甲双胍，使血糖控制不足患者的血糖水平降低了1.7%。利拉利汀/盐酸二甲双胍未引发任何显着的体重变化，不仅可以单独使用，还可与磺脲（sulphonylurea）联合用药。磺脲是2型糖尿病患者常用的处方药。
"CHMP对Jentadueto的积极意见，标志着勃林格殷格翰和礼来全球糖尿病联盟取得的另一个重要监管里程碑。在整个欧洲，许多2型糖尿病患者需要多种药物来充分控制其病情。作为一种单一片剂药物，我们认为，Jentadueto将有助于帮助2型糖尿病患者取得并维持良好的血糖控制，并改善患者的整体健康。"
Jentadueto是一种口服片剂，每日服用2次
适应症
JENTADUETO是一种二肽基肽酶-4（DPP-4）抑制剂和双胍类组合产品表示作为辅助饮食和运动改善血糖控制在成人2型糖尿病时，既linagliptin的和二甲双胍治疗为宜
使用重要的限制：
不治疗1型糖尿病或糖尿病酮症酸中毒
尚未研究的患者胰腺炎病史
剂量与用法
个性JENTADUETO基于患者的当前治疗方案的起始剂量
最大推荐剂量是2.5毫克linagliptin/1000毫克二甲双胍，每日两次.
应随餐服用，每天给予两次，逐渐增加剂量，以减少由于二甲双胍的胃肠道不良反应.
剂型和规格
片剂：
2.5毫克linagliptin/500毫克盐酸二甲双胍
2.5毫克linagliptin/850毫克盐酸二甲双胍
2.5毫克linagliptin/1000毫克的二甲双胍盐酸盐
禁忌
肾功能不全.
代谢性酸中毒，包括糖尿病酮症酸中毒.
过敏反应利拉利汀，如过敏反应，血管性水肿，剥脱性皮肤疾病，荨麻疹，或支气管高反应性的病史
过敏二甲双胍
警告和注意事项
乳酸性酸中毒：警告反对过度饮酒。 JENTADUETO不建议在肝功能不全或缺氧状态，并禁用于肾功能损害。启动之后每年至少保证前肾功能正常。
曾有急性胰腺炎的上市后报告，包括致命的胰腺炎。如果胰腺炎怀疑，请立即停止JENTADUETO。
暂时停止JENTADUETO在患者接受放射学检查与碘对比材料或任何外科手术需要粮食和液体的限制摄取血管内给药
低血糖：当与胰岛素促分泌剂（例如，磺酰脲（SU）或胰岛素使用，考虑降低胰岛素促分泌剂或胰岛素的剂量，以减少低血糖（2.2，5.5的风险）
已经出现了与利拉利汀包括过敏症，血管性水肿，和剥脱皮肤状况（JENTADUETO的元件之一）治疗的患者中严重的过敏反应上市后报告。在这种情况下，及时停止JENTADUETO，评估其他潜在原因，制定适当的监测和治疗，并开始糖尿病的替代治疗。
维生素B12缺乏：二甲双胍可降低维生素B12水平。每年监测血液学参数.
大血管病变的结果：大血管风险减少与JENTADUETO或任何其它抗糖尿病药物无确凿证据
不良反应
报道与JENTADUETO治疗的患者≥5％的不良反应，比用安慰剂治疗的患者更常见的是鼻咽炎和腹泻
低血糖更常见的与JENTADUETO和苏的组合治疗的患者与那些有SU和二甲双胍的联合治疗相比，
为报告怀疑不良反应，联系勃林格殷格翰制药公司在1-800-542-6257或1-800-459-9906 TTY，或FDA电话1-800-FDA-1088或www.fda.gov/ MedWatch通报。
药物相互作用
由肾小管分泌消除阳离子药物：可降低二甲双胍消除。请谨慎使用。
强P-glycoprotein/CYP3A4诱导剂：当在组合（例如利福平）施用JENTADUETO的疗效可能降低。使用替代疗法，强烈推荐。
特殊人群中使用
妊娠：在妊娠妇女中没有适当和对照良好的研究。 JENTADUETO片应在怀孕只有在确实需要时使用。
哺乳母亲：当JENTADUETO被给予哺乳妇女应谨慎行事.

Jentadueto 2.5 mg/850 mg film-coated tablets
Jentadueto 2.5 mg/1000 mg film-coated tablets

1. Name of the medicinal product
Jentadueto 2.5 mg/1,000 mg film-coated tablets
2. Qualitative and quantitative composition
Each tablet contains 2.5 mg of linagliptin and 1,000 mg of metformin hydrochloride.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet).
Oval, biconvex, light pink, film-coated tablet of 21.1 mm x 9.7 mm debossed with ”D2/1000" on one side and the company logo on the other.
4. Clinical particulars
4.1 Therapeutic indications
Treatment of adult patients with type 2 diabetes mellitus:
Jentadueto is indicated as an adjunct to diet and exercise to improve glycaemic control in adult patients inadequately controlled on their maximal tolerated dose of metformin alone, or those already being treated with the combination of linagliptin and metformin.
Jentadueto is indicated in combination with a sulphonylurea (i.e. triple combination therapy) as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea.
Jentadueto is indicated in combination with insulin (i.e. triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in adult patients when insulin and metformin alone do not provide adequate glycaemic control.
4.2 Posology and method of administration
Posology
The dose of antihyperglycaemic therapy with Jentadueto should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability, while not exceeding the maximum recommended daily dose of 5 mg linagliptin plus 2,000 mg of metformin hydrochloride.
For patients inadequately controlled on maximal tolerated dose of metformin monotherapy

For patients not adequately controlled on metformin alone, the usual starting dose of Jentadueto should provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose) plus the dose of metformin already being taken.
For patients switching from co-administration of linagliptin and metformin
For patients switching from co-administration of linagliptin and metformin, Jentadueto should be initiated at the dose of linagliptin and metformin already being taken.
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a sulphonylurea
The dose of Jentadueto should provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose) and a dose of metformin similar to the dose already being taken. When linagliptin plus metformin hydrochloride is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the risk of hypoglycaemia (see section 4.4).
For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose of metformin
The dose of Jentadueto should provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose) and a dose of metformin similar to the dose already being taken. When linagliptin plus metformin hydrochloride is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia (see section 4.4).
For the different doses of metformin, Jentadueto is available in strengths of 2.5 mg linagliptin plus 850 mg metformin hydrochloride and 2.5 mg linagliptin plus 1,000 mg metformin hydrochloride.
Special populations
Older people
As metformin is excreted by the kidney, Jentadueto should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the older people (see sections 4.3 and 4.4). Clinical experience with patients > 80 years of age is limited and caution should be exercised when treating this population.
Renal impairment
Jentadueto must not be used in patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min) due to the active substance metformin (see sections 4.3 and 4.4).
Hepatic impairment
Jentadueto is not recommended in patients with hepatic impairment due to the active substance metformin (see sections 4.3 and 5.2). Clinical experience with Jentadueto in patients with hepatic impairment is lacking.
Paediatric population
The safety and efficacy of Jentadueto in children and adolescents aged 0 to 18 years have not been established. No data are available.
Method of administration
Jentadueto should be taken twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin.
All patients should continue their diet with an adequate distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
If a dose is missed, it should be taken as soon as the patient remembers. However, a double dose should not be taken at the same time. In that case, the missed dose should be skipped.
4.3 Contraindications
• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
• Diabetic ketoacidosis, diabetic pre-coma.
• Renal failure or renal dysfunction (creatinine clearance < 60 ml/min).
• Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock.
• Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial infarction, shock.
• Hepatic impairment, acute alcohol intoxication, alcoholism (see section 4.5).
4.4 Special warnings and precautions for use
General
Jentadueto should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hypoglycaemia
When linagliptin was added to a sulphonylurea on a background of metformin, the incidence of hypoglycaemia was increased over that of placebo.
Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised when Jentadueto is used in combination with a sulphonylurea and/or insulin. A dose reduction of the sulphonylurea or insulin may be considered (see section 4.2).
Hypoglycaemia is not identified as adverse reaction for linagliptin, metformin, or linagliptin plus metformin. In clinical trials, the incidence rates of hypoglycemia were comparably low in patients taking linagliptin in combination with metformin or metformin alone.
Lactic acidosis
Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin hydrochloride accumulation. Reported cases of lactic acidosis in patients on metformin hydrochloride have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any condition associated with hypoxia.
Diagnosis
The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders such as abdominal pain and severe asthenia.
Lactic acidosis is characterised by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin hydrochloride should be discontinued and the patient should be hospitalised immediately (see section 4.9).
Renal function
As metformin hydrochloride is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter:
• at least annually in patients with normal renal function,
• at least two to four times a year in patients with serum creatinine levels at or above the upper limit of normal and in older subjects.
Decreased renal function in older subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy or when starting therapy with a non-steroidal anti-inflammatory substance.
Surgery
As Jentadueto contains metformin hydrochloride the treatment must be discontinued 48 hours before elective surgery with general, spinal or epidural anaesthesia. Therapy with Jentadueto should usually not be resumed earlier than 48 hours following surgery and only after renal function has been re-evaluated and found to be normal.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiologic studies can lead to renal failure which has been associated with lactic acidosis in patients receiving metformin. Therefore, Jentadueto must be discontinued prior to, or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).
Older people
Caution should be exercised when treating patients 80 years and older (see section 4.2).
Change in clinical status of patients with previously controlled type 2 diabetes
As Jentadueto contains metformin, a patient with previously well controlled type 2 diabetes on Jentadueto who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Jentadueto must be stopped immediately and other appropriate corrective measures initiated.
Pancreatitis
In post-marketing experience of linagliptin there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of linagliptin. If pancreatitis is suspected, Jentadueto should be discontinued.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacokinetic drug interaction studies with Jentadueto have not been performed; however, such studies have been conducted with the individual active substances, i.e. linagliptin and metformin. Co-administration of multiple doses of linagliptin and metformin did not meaningfully alter the pharmacokinetics of either linagliptin or metformin in healthy volunteers and patients.
Linagliptin
In vitro assessment of interactions
Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes.
Linagliptin is a P-glycoprotein substrate, and inhibits P-glycoprotein mediated transport of digoxin with low potency. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates.
In vivo assessment of interactions
Effects of other medicinal products on linagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions by coadministered medicinal products is low.
Metformin
Co-administration of multiple three-times-daily doses of 850 mg metformin hydrochloride with 10 mg linagliptin once daily did not clinical meaningfully alter the pharmacokinetics of linagliptin in healthy subjects.
Sulphonylureas
The steady-state pharmacokinetics of 5 mg linagliptin were not changed by concomitant administration of a single 1.75 mg dose glibenclamide (glyburide).
Ritonavir
Co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral doses of ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, increased the AUC and Cmax of linagliptin approximately twofold and threefold, respectively. The unbound concentrations, which are usually less than 1% at the therapeutic dose of linagliptin, were increased 4-5-fold after co-administration with ritonavir. Simulations of steady-state plasma concentrations of linagliptin with and without ritonavir indicated that the increase in exposure will not be associated with an increased accumulation. These changes in linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore, clinically relevant interactions would not be expected with other P-glycoprotein/CYP3A4 inhibitors.
Rifampicin
Multiple co-administration of 5 mg linagliptin with rifampicin, a potent inductor of P-glycoprotein and CYP3A4, resulted in a 39.6% and 43.8% decreased linagliptin steady-state AUC and Cmax respectively, and about 30% decreased DPP-4 inhibition at trough. Thus full efficacy of linagliptin in combination with strong P-gp inducers might not be achieved, particularly if these are administered long-term. Co-administration with other potent inducers of P-glycoprotein and CYP3A4, such as carbamazepine, phenobarbital and phenytoin has not been studied.
Effects of linagliptin on other medicinal products
In clinical studies, as described below, linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glyburide, simvastatin, warfarin, digoxin or oral contraceptives providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-glycoprotein, and organic cationic transporter (OCT).
Metformin
Co-administration of multiple daily doses of 10 mg linagliptin with 850 mg metformin hydrochloride, an OCT substrate, had no relevant effect on the pharmacokinetics of metformin in healthy subjects. Therefore, linagliptin is not an inhibitor of OCT-mediated transport.
Sulphonylureas
Co-administration of multiple oral doses of 5 mg linagliptin and a single oral dose of 1.75 mg glibenclamide (glyburide) resulted in clinically not relevant reduction of 14% of both AUC and Cmax of glibenclamide. Because glibenclamide is primarily metabolised by CYP2C9, these data also support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically meaningful interactions would not be expected with other sulphonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glibenclamide, are primarily eliminated by CYP2C9.
Digoxin
Co-administration of multiple daily doses of 5 mg linagliptin with multiple doses of 0.25 mg digoxin had no effect on the pharmacokinetics of digoxin in healthy subjects. Therefore, linagliptin is not an inhibitor of P-glycoprotein-mediated transport in vivo.
Warfarin
Multiple daily doses of 5 mg linagliptin did not alter the pharmacokinetics of S(-) or R(+) warfarin, a CYP2C9 substrate, administered in a single dose.
Simvastatin
Multiple daily doses of linagliptin had a minimal effect on the steady-state pharmacokinetics of simvastatin, a sensitive CYP3A4 substrate, in healthy subjects. Following administration of a supratherapeutic dose of 10 mg linagliptin concomitantly with 40 mg of simvastatin daily for 6 days, the plasma AUC of simvastatin was increased by 34%, and the plasma Cmax by 10%.
Oral contraceptives
Co-administration with 5 mg linagliptin did not alter the steady-state pharmacokinetics of levonorgestrel or ethinylestradiol.
Metformin
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
Combinations not recommended
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic impairment due to the metformin active substance (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems.
The intravascular administration of iodinated contrast agents in radiological studies may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Therefore, Jentadueto must be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.4).
4.6 Fertility, pregnancy and lactation
Pregnancy
The use of linagliptin has not been studied in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
A limited amount of data suggests that the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3).
Non-clinical reproduction studies did not indicate an additive teratogenic effect attributed to the co-administration of linagliptin and metformin.
Jentadueto should not be used during pregnancy. If the patient plans to become pregnant, or if pregnancy occurs, treatment with Jentadueto should be discontinued and switched to insulin treatment as soon as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.
Breast-feeding
Studies in animals have shown excretion of both metformin and linagliptin into milk in lactating rats. Metformin is excreted in human milk in small amounts. It is not known whether linagliptin is excreted into human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Jentadueto therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
No studies on the effect on human fertility have been conducted for Jentadueto. No adverse effects of linagliptin on fertility were observed in male or female rats (see section 5.3).
4.7 Effects on ability to drive and use machines
Jentadueto has no or negligible influence on the ability to drive and use machines. However, patients should be alerted to the risk of hypoglycaemia when Jentadueto is used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. sulphonylureas).
4.8 Undesirable effects
Summary of the safety profile
Fixed dose combination
The most frequently reported adverse reaction for linagliptin plus metformin was diarrhoea (0.9%) with a comparable rate on metformin plus placebo (1.2%).
Hypoglycaemia may occur when Jentadueto is administered together with sulphonylurea (≥ 1 case per 10 patients).
The safety of linagliptin 2.5 mg twice daily (or its bioequivalent of 5 mg once daily) in combination with metformin has been evaluated in over 3500 patients with type 2 diabetes mellitus. In placebo-controlled studies, more than 1300 patients were treated with the therapeutic dose of either 2.5 mg linagliptin twice daily (or its bioequivalent of 5 mg linagliptin once daily) in combination with metformin for ≥ 12/24 weeks.
In the pooled analysis of the four placebo-controlled trials, the overall incidence of adverse reactions in patients treated with placebo and metformin was comparable to that seen with linagliptin 2.5 mg and metformin (50.6 and 47.8%). Discontinuation of therapy due to adverse reactions was comparable in patients who received placebo and metformin to patients treated with linagliptin and metformin (2.6% and 2.3%).
Adverse reactions reported when linagliptin and metformin were combined with sulphonylurea
In one study linagliptin was given as add-on to metformin plus sulphonylurea. When linagliptin and metformin were administered in combination with a sulphonylurea, hypoglycaemia was the most frequently reported adverse reaction (linagliptin plus metformin plus sulphonylurea 22.9% versus 14.8% in placebo plus metformin plus sulphonylurea).
Adverse reactions reported when linagliptin and metformin were combined with insulin
When linagliptin and metformin were administered in combination with insulin, hypoglycaemia was the most frequently reported adverse reaction, but occurred at comparable rate when placebo and metformin were combined with insulin (linagliptin plus metformin plus insulin 29.5% versus 30.9% in the placebo plus metformin plus insulin group) with a low rate of severe episodes (1.5% versus 0.9%).
Tabulated list of adverse reactions
Adverse reactions reported with the fixed dose combination
Adverse reactions reported in all clinical trials with Jentadueto are shown below according to system organ class. Adverse reactions known to occur with each active substance given singly, but which have not been seen in clinical trials with Jentadueto, may occur during treatment with this medicinal product.
The adverse reactions are listed by system organ class and absolute frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), or very rare (< 1/10,000) and not known (cannot be estimated from the available data).
Table 1 Adverse reactions reported in patients who received Jentadueto (frequencies identified from pooled analysis of placebo-controlled studies) in clinical trial and from post-marketing experience

System organ class Adverse reaction	Adverse reactions by treatment regimen linagliptin plus metformin
Infections and infestations
Nasopharyngitis	uncommon
Immune system disorders
Hypersensitivity (e.g. bronchial hyperreactivity)	rare
Respiratory, thoracic and mediastinal disorders
Cough	uncommon
Gastrointestinal disorders
Decreased appetite	uncommon
Diarrhoea	uncommon
Nausea	uncommon
Pancreatitis	not known
Vomiting	uncommon
Skin and subcutaneous tissue disorders
Angioedema*	rare
Urticaria*	rare
Rash*	uncommon
Pruritus	uncommon
Investigations
Blood amylase increased	uncommon

* Based on post-marketing experience
Adverse reactions reported when linagliptin and metformin were combined with sulphonylurea
When linagliptin and metformin were administered in combination with a sulphonylurea, hypoglycaemia was identified as an additional adverse reaction under these conditions.
Table 2 Adverse reactions additionally reported in patients when linagliptin and metformin were combined with sulphonylurea*:

System organ class Adverse reaction	Adverse reactions by treatment regimen linagliptin plus metformin plus sulphonylurea
Metabolism and nutrition disorders
Hypoglycaemia	very common

* Refer to Summary of Product Characteristics for specific sulphonylurea for additional information
None of the hypoglycaemias was classified as severe.
Adverse reactions reported when linagliptin and metformin were combined with insulin
When linagliptin and metformin were administered in combination with insulin, constipation was identified as an additional adverse reaction under these conditions. The combination of linagliptin and metformin when administered in combination with insulin may be associated with an increased risk of hepatic events.
Table 3 Adverse reactions additionally reported in patients when linagliptin and metformin were combined with insulin*:

System organ class Adverse reaction	Adverse reactions by treatment regimen linagliptin plus metformin plus insulin
Gastrointestinal disorders
Constipation	uncommon
Hepatobiliary disorders
Liver function disorders*	common**

* Refer to Summary of Product Characteristics for insulin and metformin for additional information
** This frequency is calculated from a pooled dataset of 549 patients
Additional information on individual components
Adverse reactions previously reported with one of the individual active substances may be potential adverse reactions with Jentadueto, even if not observed in clinical trials with this medicinal product.
Linagliptin:
All identified adverse reactions of linagliptin monotherapy are also described for Jentadueto in Table 1.
Metformin:
Known adverse reactions for metformin, that were not reported in patients who received Jentadueto are listed in Table 4.
Table 4 Adverse reactions reported in patients who received metformin* as monotherapy and that were not observed in patients receiving Jentadueto

System organ class Adverse reaction	Adverse reactions by treatment regimen metformin monotherapy
Metabolism and nutrition disorders
Lactic acidosis	very rare
Vitamin B12 deficiency	very rare
Nervous system disorder
Taste disturbance	common
Gastrointestinal disorders
Abdominal pain	very common
Hepatobiliary disorders
Hepatitis	very rare
Skin and subcutaneous tissue disorders
Skin reactions such as erythema, urticaria	very rare

* Refer to Summary of Product Characteristics for metformin for additional information
Description of selected adverse reactions
Gastrointestinal disorders such as, nausea, vomiting, diarrhoea and decreased appetite (Table 1) and abdominal pain (Table 3) occur most frequently during initiation of therapy with Jentadueto or metformin hydrochloride and resolve spontaneously in most cases. For prevention, it is recommended that Jentadueto be taken in 2 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption (table 3) which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
Pharmacovigilance Section
Irish Medicines Board
Kevin O'Malley House
Earlsfort Centre
Earlsfort Terrace
Dublin 2
Ireland
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie
Malta
ADR Reporting
The Medicines Authority
Post-Licensing Directorate
203 Level 3, Rue D'Argens
GŻR-1368 Gżira
Website: www.medicinesauthority.gov.mt
e-mail: postlicensing.medicinesauthority@gov.mt
4.9 Overdose
No data are available with regard to overdose of Jentadueto.
Linagliptin
During controlled clinical trials in healthy subjects, single doses of up to 600 mg linagliptin (equivalent to 120 times the recommended dose) were not associated with a dose dependent increase in adverse events. There is no experience with doses above 600 mg in humans.
Metformin
Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin hydrochloride or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin hydrochloride is haemodialysis.
Management
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g. remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute clinical measures if required.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering drugs, ATC code: A10BD11.
Mechanism of action and pharmacodynamic effects
Jentadueto combines two antihyperglycaemic medicinal products with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: linagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Linagliptin
Linagliptin is an inhibitor of the enzyme DPP-4 (Dipeptidyl peptidase 4) an enzyme which is involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide). These hormones are rapidly degraded by the enzyme DPP-4. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretins are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Linagliptin binds very effectively to DPP-4 in a reversible manner and thus leads to a sustained increase and a prolongation of active incretin levels. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus resulting in an overall improvement in the glucose homeostasis. Linagliptin binds selectively to DPP-4 and exhibits a > 10,000 fold selectivity versus DPP-8 or DPP-9 activity in vitro.
Metformin
Metformin hydrochloride is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin hydrochloride may act via 3 mechanisms:
(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis,
(2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization,
(3) and delay of intestinal glucose absorption.
Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin hydrochloride increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.
In humans, independently of its action on glycaemia, metformin hydrochloride has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride reduces total cholesterol, LDL cholesterol and triglyceride levels.
Clinical efficacy and safety
Linagliptin as add-on to metformin therapy
The efficacy and safety of linagliptin in combination with metformin in patients with insufficient glycaemic control on metformin monotherapy was evaluated in a double-blind placebo-controlled study of 24 weeks duration. Linagliptin added to metformin provided significant improvements in HbA1c, (-0.64% change compared to placebo), from a mean baseline HbA1c of 8%. Linagliptin also showed significant improvements in fasting plasma glucose (FPG) by -21.1 mg/dl and 2-hour post-prandial glucose (PPG) by -67.1 mg/dl compared to placebo, as well as a greater portion of patients achieving a target HbA1c of < 7.0% (28.3% on linagliptin versus 11.4% on placebo). The observed incidence of hypoglycaemia in patients treated with linagliptin was similar to placebo. Body weight did not differ significantly between the groups.
In a 24-week placebo-controlled factorial study of initial therapy, linagliptin 2.5 mg twice daily in combination with metformin (500 mg or 1,000 mg twice daily) provided significant improvements in glycemic parameters compared with either monotherapy as summarised in Table 5 (mean baseline HbA1c 8.65%).
Table 5: Glycemic Parameters at Final Visit (24-Week Study) for Linagliptin and Metformin, Alone and in Combination in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise

Placebo	Linagliptin 5 mg Once Daily1	Metformin HCl 500 mg Twice Daily	Linagliptin 2.5 mg Twice Daily1 + Metformin HCl 500 mg Twice Daily	Metformin HCl 1,000 mg Twice Daily	Linagliptin 2.5 mg Twice Daily1 + Metformin HCl 1,000 mg Twice Daily
HbA1c (%)
Number of patients	n = 65	n = 135	n = 141	n = 137	n = 138	n = 140
Baseline (mean)	8.7	8.7	8.7	8.7	8.5	8.7
Change from baseline (adjusted mean)	0.1	-0.5	-0.6	-1.2	-1.1	-1.6
Difference from placebo (adjusted mean) (95% CI)	--	-0.6 (-0.9, -0.3)	-0.8 (-1.0, -0.5)	-1.3 (-1.6, -1.1)	-1.2 (-1.5, -0.9)	-1.7 (-2.0, -1.4)
Patients (n, %) achieving HbA1c <7%	7 (10.8)	14 (10.4)	27 ( 19.1)	42 (30.7)	43 (31.2)	76 (54.3)
Patients (%) receiving rescue treatment	29.2	11.1	13.5	7.3	8.0	4.3
FPG (mg/dL)
Number of patients	n = 61	n = 134	n = 136	n = 135	n = 132	n = 136
Baseline (mean)	203	195	191	199	191	196
Change from baseline (adjusted mean)	10	-9	-16	-33	-32	-49
Difference from placebo (adjusted mean) (95% CI)	--	-19 (-31, -6)	-26 (-38, -14)	-43 (-56, -31)	-42 (-55, -30)	-60 (-72, -47)

1 Total daily dose of linagliptin is equal to 5 mg
Mean reductions from baseline in HbA1c were generally greater for patients with higher baseline HbA1c values. Effects on plasma lipids were generally neutral. The decrease in body weight with the combination of linagliptin and metformin was similar to that observed for metformin alone or placebo; there was no change in weight from baseline for patients on linagliptin alone. The incidence of hypoglycaemia was similar across treatment groups (placebo 1.4%, linagliptin 5 mg 0%, metformin 2.1%, and linagliptin 2.5 mg plus metformin twice daily 1.4%).
The efficacy and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in combination with metformin in patients with insufficient glycaemic control on metformin monotherapy was evaluated in a double-blind placebo-controlled study of 12 weeks duration. Linagliptin 5 mg once daily and 2.5 mg twice daily provided comparable (CI: -0.07; 0.19) significant HbA1c reductions of -0.80% (from baseline 7.98%), and -0.74% (from baseline 7.96%) compared to placebo. The observed incidence of hypoglycaemia in patients treated with linagliptin was similar to placebo. Body weight did not differ significantly between the groups.
Linagliptin as add-on to a combination of metformin and sulphonylurea therapy
A placebo-controlled study of 24 weeks in duration was conducted to evaluate the efficacy and safety of linagliptin 5 mg to placebo, in patients not sufficiently treated with a combination with metformin and a sulphonylurea. Linagliptin provided significant improvements in HbA1c (-0.62% change compared to placebo), from a mean baseline HbA1c of 8.14%. Linagliptin also showed significant improvements in patients achieving a target HbA1c of < 7.0% (31.2% on linagliptin versus 9.2% on placebo), and also for fasting plasma glucose (FPG) with -12.7 mg/dl reduction compared to placebo. Body weight did not differ significantly between the groups.
Linagliptin in combination with metformin and insulin
A 24-week placebo-controlled study was conducted to evaluate the efficacy and safety of linagliptin (5 mg once daily) added to insulin with or without metformin. 83% of patients were taking metformin in combination with insulin in this trial. Linagliptin in combination with metformin plus insulin provided significant improvements in HbA1c in this subgroup with -0.68% (CI: -0.78; -0,57) adjusted mean change from baseline (mean baseline HbA1c 8.28%) compared to placebo in combination with metformin plus insulin. There was no meaningful change from baseline in body weight in either group.
Linagliptin 24 month data, as add-on to metformin in comparison with glimepiride
In a study comparing the efficacy and safety of the addition of linagliptin 5 mg or glimepiride (mean dose 3 mg) in patients with inadequate glycaemic control on metformin monotherapy, mean reductions in HbA1c were -0.16% with linagliptin (mean baseline HbA1c 7.69%) and -0.36% with glimepiride (mean baseline HbA1c 7.69%.) with a mean treatment difference of 0.20% (97.5% CI: 0.09, 0.299). The incidence of hypoglycaemia in the linagliptin group (7.5%) was significantly lower than that in the glimepiride group (36.1%). Patients treated with linagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glimepiride (-1.39 versus +1.29 kg).
Linagliptin as add-on therapy in older people (age ≥ 70 years) with type 2 diabetes
The efficacy and safety of linagliptin in older people (age ≥ 70years) with type 2 diabetes was evaluated in a double-blind study of 24 weeks duration. Patients received metformin and/or sulphonylurea and/or insulin as background therapy. Doses of background antidiabetic medications were kept stable during the first 12 weeks, after which adjustments were permitted. Linagliptin provided significant improvements in HbA1c (-0.64% change compared to placebo after 24 weeks), from a mean baseline HbA1c of 7.8%. Linagliptin also showed significant improvements in fasting plasma glucose (FPG) compared to placebo. Body weight did not differ significantly between the groups.
In a pooled analysis of elderly (age ≥ 70 years) patients with type 2 diabetes (n=183) who were taking both metformin and basal insulin as background therapy, linagliptin in combination with metformin plus insulin provided significant improvements in HbA1c parameters with -0.81% (CI: -1.01; -0.61) adjusted mean change from baseline (mean baseline HbA1c 8.13%) compared to placebo in combination with metformin plus insulin.
Cardiovascular risk
In a prospective meta-analysis of independently adjudicated cardiovascular events from 19 clinical studies (ranging from 18 weeks to 24 months duration) involving 9459 patients with type 2 diabetes, linagliptin treatment was not associated with an increase in cardiovascular risk. The primary endpoint, the composite of the occurrence or time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina, was non-significantly lower for linagliptin versus combined active and placebo comparators [Hazard ratio 0.78 (95% confidence interval 0.55;1.12)]. In total there were 60 primary events on linagliptin and 62 on comparators. To date there is no evidence for an increased CV risk but the number of events in the clinical studies precludes firm conclusions. However, cardiovascular events were similar between linagliptin and placebo (1.03% with linagliptin versus 1.35% with placebo).
Metformin
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:
• a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034,
• a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017,
• a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021),
• a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of the studies with Jentadueto in all subsets of the paediatric population in type 2 diabetes (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Jentadueto
Bioequivalence studies in healthy subjects demonstrated that the Jentadueto (linagliptin/metformin hydrochloride) combination tablets are bioequivalent to co-administration of linagliptin and metformin hydrochloride as individual tablets.
Administration of Jentadueto 2.5/1,000 mg with food resulted in no change in overall exposure of linagliptin. With metformin there was no change in AUC, however mean peak serum concentration of metformin was decreased by 18% when administered with food. A delayed time to peak serum concentrations by 2 hours was observed for metformin under fed conditions. These changes are not likely to be clinically meaningful.
The following statements reflect the pharmacokinetic properties of the individual active substances of Jentadueto
Linagliptin:
The pharmacokinetics of linagliptin has been extensively characterised in healthy subjects and patients with type 2 diabetes. After oral administration of a 5 mg dose to healthy volunteers or patients, linagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1.5 hours post-dose.
Plasma concentrations of linagliptin decline in a triphasic manner with a long terminal half-life (terminal half-life for linagliptin more than 100 hours), that is mostly related to the saturable, tight binding of linagliptin to DPP-4 and does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of 5 mg linagliptin, is approximately 12 hours. After once daily dosing of 5 mg linagliptin, steady-state plasma concentrations are reached by the third dose. Plasma AUC of linagliptin increased approximately 33% following 5 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Due to the concentration dependent binding of linagliptin to DPP-IV, the pharmacokinetics of linagliptin based on total exposure is not linear; indeed total plasma AUC of linagliptin increased in a less than dose-proportional manner, while unbound AUC increases in a roughly dose-proportional manner. The pharmacokinetics of linagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.
Absorption
The absolute bioavailability of linagliptin is approximately 30%. Co-administration of a high-fat meal with linagliptin prolonged the time to reach Cmax by 2 hours and lowered Cmax by 15%, but no influence on AUC 0-72h was observed. No clinically relevant effect of Cmax and Tmax changes is expected; thereforelinagliptin may be administered with or without food.
Distribution
As a result of tissue binding, the mean apparent volume of distribution at steady-state following a single 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1110 litres, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/l to 75-89% at ≥ 30 nmol/l, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin At high concentrations, where DPP-4 is fully saturated, 70-80% of linagliptin was bound to other plasma proteins than DPP-4, hence 30-20% were unbound in plasma.
Biotransformation
Following a [14C] linagliptin oral 10 mg dose, approximately 5% of the radioactivity was excreted in urine. Metabolism plays a subordinate role in the elimination of linagliptin. One main metabolite with a relative exposure of 13.3% of linagliptin at steady-state was detected which was found to be pharmacologically inactive, and thus does not contribute to the plasma DPP-4 inhibitory activity of linagliptin.
Elimination
Following administration of an oral [14C] linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated in faeces (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 ml/min.
Special populations
Renal impairment
Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects. In moderate renal impairment, a moderate increase in exposure of about 1.7 fold was observed compared with control. Exposure in T2DM patients with severe RI was increased by about 1.4 fold compared to T2DM patients with normal renal function. Steady-state predictions for AUC of linagliptin in patients with ESRD indicated comparable exposure to that of patients with moderate or severe renal impairment. In addition, linagliptin is not expected to be eliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis. No dose adjustment of linagliptin is recommended in patients with renal impairment; therefore, linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if Jentadueto is discontinued due to evidence of renal impairment.
Hepatic impairment
In patients with mild moderate and severe hepatic impairment (according to the Child-Pugh classification), mean AUC and Cmax of linagliptin were similar to healthy matched controls following administration of multiple 5 mg doses of linagliptin.
Body Mass Index (BMI)
Body mass index had no clinically relevant effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. The clinical trials before marketing authorization have been performed up to a BMI equal to 40 kg/m2.
Gender
Gender had no clinically relevant effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data.
Older people
Age did not have a clinically relevant impact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. Older subjects (65 to 80 years, oldest patient was 78 years) had comparable plasma concentrations of linagliptin compared to younger subjects. Linagliptin trough concentrations were also measured in older people (age ≥ 70 years) with type 2 diabetes in a phase III study of 24 weeks duration. Linagliptin concentrations in this study were within the range of values previously observed in younger type 2 diabetes patients.
Paediatric population
Studies characterizing the pharmacokinetics of linagliptin in paediatric patients have not been yet performed.
Race
Race had no obvious effect on the plasma concentrations of linagliptin based on a composite analysis of available pharmacokinetic data, including patients of Caucasian, Hispanic, African, and Asian origin. In addition the pharmacokinetic characteristics of linagliptin were found to be similar in dedicated phase I studies in Japanese, Chinese and Caucasian healthy subjects and African American type 2 diabetes patients.
Metformin:
Absorption
After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin hydrochloride absorption are non-linear.
At the recommended metformin hydrochloride doses and dosing schedules, steady-state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum metformin hydrochloride plasma levels (Cmax) did not exceed 5 microgram/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
Distribution
Plasma protein binding is negligible. Metformin hydrochloride partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 l.
Biotransformation
Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
Renal clearance of metformin hydrochloride is > 400 ml/min, indicating that metformin hydrochloride is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin hydrochloride in plasma.
Special populations
Paediatric population
Single dose study: after single doses of metformin hydrochloride 500 mg, paediatric patients have shown a similar pharmacokinetic profile to that observed in healthy adults.
Multiple-dose study: data are restricted to one study. After repeated doses of 500 mg twice daily for 7 days in paediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.
5.3 Preclinical safety data
Linagliptin plus metformin
General toxicity studies in rats for up to 13 weeks were performed with the co-administration of linagliptin and metformin. The only observed interaction between linagliptin and metformin was a reduction of body weight gain. No other additive toxicity caused by the combination of linagliptin and metformin was observed at AUC exposure levels up to 2 and 23 times human exposure, respectively.
An embryofetal development study in pregnant rats did not indicate a teratogenic effect attributed to the co-administration of linagliptin and metformin at AUC exposure levels up to 4 and 30 times human exposure, respectively.
Linagliptin
Liver, kidneys and gastrointestinal tract are the principal target organs of toxicity in mice and rats at repeat doses of linagliptin of more than 300 times the human exposure.
In rats, effects on reproductive organs, thyroid and the lymphoid organs were seen at more than 1500 times human exposure. Strong pseudo-allergic reactions were observed in dogs at medium doses, secondarily causing cardiovascular changes, which were considered dog-specific. Liver, kidneys, stomach, reproductive organs, thymus, spleen, and lymph nodes were target organs of toxicity in Cynomolgus monkeys at more than 450 times human exposure. At more than 100 times human exposure, irritation of the stomach was the major finding in these monkeys.
Linagliptin and its main metabolite did not show a genotoxic potential.
Oral 2 year carcinogenicity studies in rats and mice revealed no evidence of carcinogenicity in rats or male mice. A significantly higher incidence of malignant lymphomas only in female mice at the highest dose (> 200 times human exposure) is not considered relevant for humans (explanation: non-treatment related but due to highly variable background incidence). Based on these studies there is no concern for carcinogenicity in humans.
The NOAEL for fertility, early embryonic development and teratogenicity in rats was set at > 900 times the human exposure. The NOAEL for maternal-, embryo-fetal-, and offspring toxicity in rats was 49 times human exposure. No teratogenic effects were observed in rabbits at > 1,000 times human exposure. A NOAEL of 78 times human exposure was derived for embryo-fetal toxicity in rabbits, and for maternal toxicity the NOAEL was 2.1 times human exposure. Therefore, it is considered unlikely that linagliptin affects reproduction at therapeutic exposures in humans.
Metformin
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or reproductive toxicity.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Arginine
Copovidone
Magnesium stearate
Maize starch
Silica, colloidal anhydrous
Film coating
Hypromellose
Titanium dioxide (E171)
Talc
Iron oxide, red (E172)
Propylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Blister
Store in the original package in order to protect from moisture.
Bottle
Keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
Pack sizes of 10 x 1, 14 x 1, 28 x 1, 30 x 1, 56 x 1, 60 x 1, 84 x 1, 90 x 1, 98 x 1, 100 x 1 and 120 x 1 film-coated tablets and multipacks containing 120 (2 packs of 60 x 1), 180 (2 packs of 90 x 1) and 200 (2 packs of 100 x 1) film-coated tablets in aluminium lidding foil and PVC/polychlorotrifluoro ethylene/PVC based forming foil perforated unit dose blisters.
HDPE bottle with plastic screw cap and a silica gel desiccant. Pack sizes of 14, 60 and 180 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Boehringer Ingelheim International GmbH,
Binger Str. 173,
D-55216 Ingelheim am Rhein,
Germany.
8. Marketing authorisation number(s)
EU/1/12/780/015 (10 x 1 film-coated tablets)
EU/1/12/780/016 (14 x 1 film-coated tablets)
EU/1/12/780/017 (28 x 1 film-coated tablets)
EU/1/12/780/018 (30 x 1 film-coated tablets)
EU/1/12/780/019 (56 x 1 film-coated tablets)
EU/1/12/780/020 (60 x 1 film-coated tablets)
EU/1/12/780/021 (84 x 1 film-coated tablets)
EU/1/12/780/022 (90 x 1 film-coated tablets)
EU/1/12/780/023 (98 x 1 film-coated tablets)
EU/1/12/780/024 (100 x 1 film-coated tablets)
EU/1/12/780/025 (120 x 1 film-coated tablets)
EU/1/12/780/026 (14 film-coated tablets, bottle)
EU/1/12/780/027 (60 film-coated tablets, bottle)
EU/1/12/780/028 (180 film-coated tablets, bottle)
EU/1/12/780/032 (120 (2 x 60 x 1) film-coated tablets)
EU/1/12/780/033 (180 (2 x 90 x 1) film-coated tablets)
EU/1/12/780/034 (200 ( 2 x 100 x 1) film-coated tablets)
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 20 July 2012
10. Date of revision of the text
01/2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.