Insulin degludec and liraglutide

7 DRUG INTERACTIONS • Drugs that affect glucose metabolism : Adjustment of XULTOPHY 100/3.6 dosage may be needed; closely monitor blood glucose. ( 7.1 ) • Anti-Adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Hypoglycemia signs and symptoms may be reduced or absent. ( 7.1 ) • Effects of delayed gastric emptying on oral medications : May impact absorption of concomitantly administered oral medications. ( 7.2 )

7.1 Medications that Can Affect Glucose Metabolism A number of medications affect glucose metabolism and may require dose adjustment of XULTOPHY 100/3.6 and particularly close monitoring [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.6 )].

Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs.

Drugs That May Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6 Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dosage increases and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs.

Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6 Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dosage adjustment and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs.

7.2 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide-containing products, including XULTOPHY 100/3.6, cause a delay of gastric emptying, and thereby have the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide containing products.

8.1 Pregnancy Risk Summary Based on animal reproduction studies, there may be risks to the fetus from exposure to liraglutide during pregnancy. XULTOPHY 100/3.6 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no available data with XULTOPHY 100/3.6, insulin degludec or liraglutide in pregnant women to inform a drug associated risk for major birth defects and miscarriage. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations).

For insulin degludec, rats and rabbits were exposed in animal reproduction studies at 5 times (rat) and 10 times (rabbit) the human exposure at a dose of

0.75 U/kg/day. No adverse outcomes were observed for pregnant animals and offspring (see Data) . For liraglutide, animal reproduction studies identified increased adverse developmental outcomes from exposure during pregnancy. Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 1.8 mg/day.

In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pregestational diabetes with a peri-conceptional HbA 1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA 1c >10.

The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo/fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, macrosomia related morbidity.

Data Animal Data Insulin degludec Insulin degludec was investigated in studies covering fertility, embryo-fetal development and pre- and post-natal development…