Onglyza · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-095372 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most commonly reported adverse reactions in placebo-controlled trials reported in ≥ 5% of patients treated with Onglyza 5 mg and more commonly than in patients treated with placebo are upper respiratory tract infection (7.7%), urinary tract infection (6.8%) and headache (6.5%). There were 4 148 patients with type 2 diabetes, including 3 021 patients treated with Onglyza, randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control. In randomised, controlled, double-blind clinical trials (including developmental and postmarketing experience), over 17 000 patients with type 2 diabetes have been treated with Onglyza. In a pooled analysis of 1 681 patients with type 2 diabetes including 882 patients treated with Onglyza 5 mg, randomised in five double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control, the overall incidence of adverse events in patients treated with saxagliptin 5 mg was similar to placebo. Discontinuation of therapy due to adverse events was higher in patients who received saxagliptin 5 mg as compared to placebo (3.3% as compared to 1.8%). Tabulated list of adverse reactions Adverse reactions reported in ≥ 5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo or that were reported in ≥ 2% of patients treated with saxagliptin 5 mg and ≥ 1% more frequently compared to placebo from the pooled analysis of five studies of glycaemic control, plus an additional active-controlled study of initial combination with metformin are shown in Table 1. 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), very rare (< 1/10 000), or not known (cannot be estimated from the available data). Table 1 Frequency of adverse reactions by system organ class from clinical trials and postmarketing experience System organ class Frequency of adverse reactions by treatment regimen Adverse reaction Saxagliptin as Saxagliptin add-on to

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HOS-095368 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, and angioedema, to any dipeptidyl peptidase-4 (DPP4) inhibitor (see sections 4.4 and 4.8).

HOS-095367 · has-indication-information · PDF-Seite 2

Onglyza is indicated in adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:  as monotherapy when metformin is inappropriate due to intolerance or contraindications.  in combination with other medicinal products for the treatment of diabetes, including insulin, when these do not provide adequate glycaemic control (see sections 4.4, 4.5 and 5.1 for available data on different combinations).

HOS-095370 · has-interaction-information · PDF-Seite 5

Clinical data described below suggest that the risk for clinically meaningful interactions with co-administered medicinal products is low. The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as carbamazepine, dexamethasone, phenobarbital and phenytoin) have not been studied and may result in decreased plasma concentration of saxagliptin and increased concentration of its major metabolite. Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent CYP3A4/5 inducer. 5 Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, increased the Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding values for the active metabolite were decreased by 44% and 34%, respectively. Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, increased the Cmax and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding values for the active metabolite were decreased by 95% and 88%, respectively. Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin, reduced Cmax and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the plasma DPP4 activity inhibition over a dose interval were not influenced by rifampicin (see section 4.4). In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. In studies conducted in healthy subjects, neither the pharmacokinetics of saxagliptin nor its major metabolite, were meaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or famotidine. In addition, saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, the active components of a combined oral contraceptive (ethinyl estradiol and norgestimate), diltiazem or ketoconazole. The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of saxagliptin have not been specifically studied.

HOS-095371 · has-pregnancy-information · PDF-Seite 6

Pregnancy The use of saxagliptin has not been studied in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Onglyza should not be used during pregnancy unless clearly necessary. Breast-feeding It is unknown whether saxagliptin is excreted in human breast milk. Animal studies have shown excretion of saxagliptin and/or metabolite in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy to the woman. Fertility The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity (see section 5.3).

HOS-095369 · has-warning-information · PDF-Seite 3

General Onglyza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. 3 Onglyza is not a substitute for insulin in insulin-requiring patients. Acute Pancreatitis Use of DPP4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominal pain. If pancreatitis is suspected, Onglyza should be discontinued; if acute pancreatitis is confirmed, Onglyza should not be restarted. Caution should be exercised in patients with a history of pancreatitis. In postmarketing experience of saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis. Renal impairment In patients with GFR < 45 mL/min, the recommended dose is 2.5 mg once daily. Saxagliptin is not recommended for use in patients with end-stage renal disease (ESRD) requiring haemodialysis. Assessment of renal function is recommended prior to initiation of Onglyza, and in keeping with routine care, renal assessment should be done periodically thereafter (see sections 4.2 and 5.2). Hepatic impairment Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is not recommended for use in patients with severe hepatic impairment (see section 4.2). Use with medicinal products known to cause hypoglycaemia Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, a lower dose of sulphonylurea or insulin may be required to reduce the risk of hypoglycaemia when used in combination with Onglyza. Hypersensitivity reactions Onglyza must not be used in patients who have had any serious hypersensitivity reaction to a dipeptidyl peptidase-4 (DPP4) inhibitor (see section 4.3). During postmarketing experience, including spontaneous reports and clinical trials, the following adverse reactions have been reported with the use of saxagliptin: serious hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, and angioedema. If a serious hypersensitivity reaction to saxagliptin is suspected, Onglyza should be discontinued, assess for other potential causes for the event, and institute alternative treatment for diabetes (see section 4.8). Skin disorders Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Skin

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