Adverse reactions : תופעות לוואי

Adverse Reactions
TRAJENTA 5mg (%)                          Placebo (%) n = 3625                                n = 2176
Nasopharyngitis                              7.0                                     6.1 Diarrhea                                     3.3                                     3.0 Cough                                        2.1                                     1.4 
Rates for other adverse reactions for TRAJENTA 5 mg vs placebo when TRAJENTA was used in combination with specific antidiabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRAJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRAJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRAJENTA was used as add-on to basal insulin therapy. Other adverse reactions reported in clinical studies with treatment of TRAJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.

Following 104 weeks’ treatment in a controlled study comparing TRAJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated with TRAJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%).

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRAJENTA compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Hypoglycemia
Table 2 summarizes the incidence of hypoglycemia in placebo-controlled studies of TRAJENTA. The incidence of hypoglycemia increased when TRAJENTA was administered with sulfonylurea or insulin.



Trajenta                                                                       Updated Prescribing Information File coated tablets 5 mg                                                                       September 2022 Table 2 Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of TRAJENTA in Patients with Type 2 Diabetes Mellitus


Add-on to Sulfonylurea (18           Placebo (N=84)                     TRAJENTA (N=161) Weeks)
Hypoglycemia with plasma            1.2                                1.9 glucose <54 mg/dL (%)
Severe* hypoglycemia (%)            0                                  0 Add-on to Metformin and              Placebo (N=263)                    TRAJENTA (N=792) Sulfonylurea (24 Weeks)
Hypoglycemia with plasma            5.3                                8.1 glucose <54 mg/dL (%)
Severe* hypoglycemia (%)            0.8                                0.6 Add-on to Basal Insulin (52          Placebo (N=630)                    TRAJENTA (N=631) Weeks)
Hypoglycemia with plasma            21.6                               19.8 glucose <54 mg/dL (%)
Severe* hypoglycemia (%)            1.1                                1.7 *Hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.


In an active-controlled (glimepiride) cardiovascular safety study with TRAJENTA (CAROLINA) with median time on treatment of 5.9 years, the incidence of severe hypoglycemia was 0.3% in the TRAJENTA group (N=3014) and 2.2% in glimepiride group (N=3000).


Use in Renal Impairment
TRAJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed.

In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRAJENTA trials. The observed incidence of hypoglycemia was higher (TRAJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRAJENTA-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) TRAJENTA-treated patients and 3 (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on TRAJENTA and 1 (1.5%) patient on placebo. Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks’ treatment compared to placebo.


Trajenta                                                                    Updated Prescribing Information File coated tablets 5 mg                                                                    September 2022 Laboratory Tests
Changes in laboratory findings were similar in patients treated with TRAJENTA 5 mg compared to patients treated with placebo.
Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the TRAJENTA group and 1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRAJENTA group).
Increase in Lipase: In a placebo-controlled clinical trial with TRAJENTA in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the TRAJENTA arm compared to a mean decrease of 2% in the placebo arm.
Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRAJENTA and placebo arms, respectively.


Increase in Amylase: In a cardiovascular safety study comparing TRAJENTA versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRAJENTA and glimepiride arms, respectively.


The clinical significance of elevations in lipase and amylase with TRAJENTA is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (8.1)].


Vital Signs
No clinically meaningful changes in vital signs were observed in patients treated with TRAJENTA.
9.2.       Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of TRAJENTA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

•       Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (4)]
•       Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
•       Severe and disabling arthralgia
•       Bullous pemphigoid
•       Rash
•       Mouth ulceration, stomatitis
•       Rhabdomyolysis 
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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/



Trajenta                                                                                 Updated Prescribing Information File coated tablets 5 mg                                                                                 September 2022 10.     DRUG INTERACTIONS

10.1 Inducers of P-glycoprotein or CYP3A4 Enzymes

Rifampin decreased linagliptin exposure, suggesting that the efficacy of TRAJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer [see Clinical Pharmacology (14.3)].
10.2 Insulin Secretagogues or Insulin

The risk of hypoglycemia is increased when linagliptin is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Coadministration of TRAJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (8.2)].

11.     USE IN SPECIFIC POPULATIONS

11.1. Pregnancy
Risk Summary
The limited data with TRAJENTA use in pregnant women are not sufficient to inform of drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

In animal reproduction studies, no adverse developmental effects were observed when linagliptin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure [see Data].

The estimated background risk of major birth defects is 6% to-10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as 20% to 25% in women with HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown. 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.

Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data
Animal Data
No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively.
These doses represent approximately 943 times (rats) and 1943 times (rabbits) the 5 mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose, based on exposure.

Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.

11.2. Lactation
Risk Summary
There is no information regarding the presence of linagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. However, linagliptin is present in rat milk. Therefore, the developmental and health 
Trajenta                                                                           Updated Prescribing Information File coated tablets 5 mg                                                                           September 2022 benefits of breastfeeding should be considered along with the mother’s clinical need for TRAJENTA and any potential adverse effects on the breastfed child from TRAJENTA or from the underlying maternal condition.

11.3. Pediatric Use
Safety and effectiveness of TRAJENTA in pediatric patients under 18 years of age have not been established.

11.4. Geriatric Use
In linagliptin studies, 1085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.

11.5. Renal Impairment
No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology (14.3)].
In the TRAJENTA treatment arm of the CARMELINA trial [see Clinical Studies (16)], 2200 (63%) patients had renal impairment (eGFR <60 mL/min/1.73 m2). Approximately 20% of the population had eGFR ≥45 to <60 mL/min/1.73 m2, 28% of the population had eGFR ≥30 to <45 mL/min/1.73 m2 and 15% had eGFR <30 mL/min/1.73 m2. The overall incidence of adverse reactions were generally similar between the TRAJENTA and placebo treatment arms.

11.6.   Hepatic Impairment

No dose adjustment is recommended for patients with hepatic impairment [see Clinical Pharmacology (14.3)].