Gibtulio

Each Gibtulio film-coated tablet contains Empagliflozin 10 or 25 mg.

It also contains the following excipients: Lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium, anhydrous colloidal silica, magnesium stearate, opadry yellow 02B38190.

Gibtulio is D-glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-(1S).

Gibtulio is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitation of Use

Gibtulio is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Gibtulio is an oral diabetes medicine that helps control blood sugar levels. Gibtulio works by helping the kidneys get rid of glucose from your bloodstream.

Gibtulio is used together with diet and exercise to treat type 2 diabetes. Gibtulio is not for treating type 1 diabetes.

Gibtulio may also be used for purposes not listed in this medication guide.

Monotherapy and Add-on Combination: Recommended Starting Dose: 10 mg Gibtulio once daily for monotherapy and add-on combination therapy with other glucose-lowering medicinal products including insulin. In patients tolerating Gibtulio 10 mg once daily who have an eGFR ≥60 ml/min/1.73 m² and need tighter glycaemic control, the dose can be increased to 25 mg once daily. The maximum daily dose is 25 mg.

When Gibtulio is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia.

Children: The safety and efficacy of Gibtulio in children and adolescents has not yet been established. No data are available.

Elderly: No dose adjustment is recommended based on age. In patients 75 years and older, an increased risk for volume depletion should be taken into account. In patients aged 85 years and older, initiation of Gibtulio therapy is not recommended due to the limited therapeutic experience.

Renal Impairment: Due to the mechanism of action, the efficacy of Gibtulio is dependent on renal function. No dose adjustment is required for patients with an eGFR ≥60 ml/min/1.73 m² or CrCl ≥60 ml/min.

Gibtulio should not be initiated in patients with an eGFR <60 ml/min/1.73 m² or CrCl <60 ml/min. In patients tolerating Gibtulio whose eGFR falls persistently below 60 ml/min/1.73 m² or CrCl below 60 ml/min, the dose of Gibtulio should be adjusted to or maintained at 10 mg once daily. Gibtulio should be discontinued when eGFR is persistently below 45 ml/min/1.73 m² or CrCl persistently below 45 ml/min.

Gibtulio should not be used in patients with end stage renal disease (ESRD) or in patients on dialysis as it is not expected to be effective in these patients.

Hepatic Impairment: No dose adjustment is required for patients with hepatic impairment. Gibtulio exposure is increased in patients with severe hepatic impairment. Therapeutic experience in patients with severe hepatic impairment is limited and therefore not recommended for use in this population.

Administration: The tablets can be taken with or without food, swallowed whole with water. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

See also:
What is the most important information I should know about Gibtulio?

Hypersensitivity to the Gibtulio or any of the excipients of Gibtulio.

In case of rare hereditary conditions that may be incompatible with an excipient of Gibtulio, the use of the Gibtulio is contraindicated.

Use Gibtulio as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Gibtulio. Talk to your pharmacist if you have questions about this information.
• Take Gibtulio by mouth in the morning with or without food.
• Check with your doctor to see if you should drink extra fluids while taking Gibtulio.
• Take Gibtulio on a regular schedule to get the most benefit from it. Taking Gibtulio at the same time each day will help you remember to take it.
• Continue to take Gibtulio even if you feel well. Do not miss any doses.
• If you miss a dose of Gibtulio, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Gibtulio.

Gibtulio is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke. Gibtulio works by increasing the removal of sugar by your kidneys.

How to use Gibtulio

Read the Patient Information Leaflet if available from your pharmacist before you start taking Gibtulio and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with or without food as directed by your doctor, usually once daily in the morning. The dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

Tell your doctor if your condition does not improve or if it worsens (such as if your blood sugar levels remain high or increase).

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What other drugs will affect Gibtulio?

Pharmacodynamic Interactions: Diuretics: Gibtulio may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension.

Insulin and Insulin Secretagogues: Insulin and insulin secretagogues, eg, sulphonylureas, may increase the risk of hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with Gibtulio.

Pharmacokinetic Interactions: Effects of Other Medicinal Products on Gibtulio: In vitro data suggest that the primary route of metabolism of Gibtulio in humans is glucuronidation by uridine 5'-diphosphoglucuronosyltransferases UGT1A3, UGT1A8, UGT1A9 and UGT2B7. Gibtulio is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Gibtulio is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Co-administration of Gibtulio with probenecid, an inhibitor of UGT enzymes and OAT3, resulted in a 26% increase in peak Gibtulio plasma concentrations (C_max) and a 53% increase in area under the concentration-time curve (AUC). These changes were not considered to be clinically meaningful.

The effect of UGT induction on Gibtulio has not been studied. Co-medication with known inducers of UGT enzymes should be avoided due to a potential risk of decreased efficacy.

An interaction study with gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that Gibtulio C_max increased by 15% and AUC increased by 59% following co-adminsitration. These changes were not considered to be clinically meaningful.

Inhibition of OATP1B1/1B3 transporters by co-administration with rifampicin resulted in a 75% increase in C_max and a 35% increase in AUC of Gibtulio. These changes were not considered to be clinically meaningful.

Gibtulio exposure was similar with and without co-administration with verapamil, a P-gp inhibitor, indicating that inhibition of P-gp does not have any clinically relevant effect on Gibtulio.

Interaction studies conducted in healthy volunteers suggest that the pharmacokinetics of Gibtulio were not influenced by co-administration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorthiazide.

Effects of Gibtulio on Other Medicinal Products: Based on in vitro studies, Gibtulio does not inhibit, inactivate or induce CYP450 isoforms. Gibtulio does not inhibit UGT1A1. Drug-drug interactions involving the major CYP450 isoforms or UGT1A1 with Gibtulio and concomitantly administered substrates of these enzymes are therefore considered unlikely. The potential for Gibtulio to inhibit UGT2B7 has not been studied.

Gibtulio does not inhibit P-gp at therapeutic doses. Based on in vitro studies, Gibtulio is considered unlikely to cause interactions with drugs that are P-gp substrates. Co-administration of digoxin, a P-gp substrate, with Gibtulio resulted in a 6% increase in AUC and 14% increase in C_max of digoxin. These changes were not considered to be clinically meaningful.

Gibtulio does not inhibit human uptake transporters eg, OAT3, OATP1B1 and OATP1B3 in vitro at clinically relevant plasma concentrations and, eg, drug-drug interactions with substrates of these uptake transporters are considered unlikely.

Interaction studies conducted in healthy volunteers suggest that Gibtulio had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, simvastatin, warfarin, ramipiril, digoxin, diuretics and oral contraceptives.

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What are the possible side effects of Gibtulio?

A total of 13,076 patients with type 2 diabetes were treated in clinical studies to evaluate the safety of Gibtulio, of which 8,400 patients were treated with Gibtulio, either alone or in combination with metformin, a sulfonylurea, a PPARγ agonist, DPP4 inhibitors, or insulin. In clinical trials 2,856 patients received treatment with Gibtulio (Gibtulio) 10 mg and 3,738 patients have received treatment with Gibtulio (Gibtulio) 25 mg for at least 24 weeks and 601 or 881 patients for at least 76 weeks.

In these trials, the frequency of AEs leading to discontinuation was similar by treatment groups for placebo (5.3%), Gibtulio 10 mg (4.8%) and Gibtulio 25 mg (4.9%).

Placebo controlled double-blinded trials of 18 to 24 weeks of exposure included 2,971 patients, of which 995 were treated with placebo, 999 were treated with Gibtulio 10 mg and 977 were treated with Gibtulio 25 mg.

The most frequent adverse drug reaction was hypoglycaemia, which depended on the type of background therapy used in the respective studies.

Description of Selected Side Effects: The frequencies are calculated for side effects regardless of causality.

Hypoglycaemia: The frequency of hypoglycaemia depended on the background therapy in the respective studies.

Minor Hypoglycaemia (Blood Glucose 54-70 mg/dL): The frequency of patients with minor hypoglycaemia was similar for Gibtulio and placebo as monotherapy, as add-on to metformin, and as add-on to pioglitazone +/- metformin.

The frequency of patients with minor hypoglycaemia was increased in patients treated with Gibtulio compared to placebo when given as add-on to metformin plus sulfonylurea (Gibtulio 10 mg 10.3%, Gibtulio 25 mg 7.4%, placebo 5.3%), and as add-on to insulin +/- metformin and +/- sulfonylurea (during initial 18 weeks treatment when insulin could not be adjusted frequency was Gibtulio 10 mg 5.9%, Gibtulio 25 mg 7.7%, placebo 5.3%; over the 78-week trial, frequency was Gibtulio 10 mg 14.2%, Gibtulio 25 mg 12.3%, placebo 12.4%).

Major Hypoglycaemia (Blood Glucose <54 mg/dL): The frequency of patients with major hypoglycaemic events was low (<1%) and similar for Gibtulio and placebo as monotherapy, as add-on to metformin, and as add on to pioglitazone +/- metformin.

The frequency of patients with major hypoglycaemic events was increased in patients treated with Gibtulio compared to placebo when given as add-on to metformin plus sulfonylurea (during initial 18 weeks treatment when insulin could not be adjusted frequency was Gibtulio 10 mg 5.8%, Gibtulio 25 mg 4.1%, placebo 3.1%), or as add-on to insulin +/- metformin and +/-sulfonylurea (Gibtulio 10 mg 13.6%, Gibtulio 25 mg 20.0%, placebo 15.3%; over the 78-week trial, frequency was Gibtulio 10 mg 21.9%, Gibtulio 25 mg 23.2%, placebo 22.9%).

Urinary Tract Infection: The overall frequency of urinary tract infection adverse events was similar in patients treated with Gibtulio 25 mg and placebo (7.6%), and higher in patients treated with Gibtulio 10 mg (9.3%). Similar to placebo, urinary tract infection was reported more frequently for Gibtulio in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary tract infections was similar to placebo for mild, moderate, and severe intensity reports. Urinary tract infection events were reported more frequently for Gibtulio compared to placebo in female patients, but not in male patients.

Vaginal Moniliasis, Vulvovaginitis, Balanitis and Other Genital Infection: Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for Gibtulio 10 mg (4.1%) and Gibtulio 25 mg (3.7%) compared to placebo (0.9%), and were reported more frequently for Gibtulio compared to placebo in female patients, and the difference in frequency was less pronounced in male patients. The genital tract infections were mild and moderate in intensity, none was severe in intensity. Standard care and treatment should be exercised when having vaginal moniliasis, vulvovaginitis, balanitis and other genital infections.

Increased Urination: As expected via its mechanism of action, increased urination (as assessed by PT search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in patients treated with Gibtulio 10 mg (3.4%) and Gibtulio 25 mg (3.2%) compared to placebo (1%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and Gibtulio (<1%).

Volume Depletion: The overall frequency of volume depletion [including the predefined terms blood pressure (ambulatory) decreased, decreased blood pressure systolic, dehydration, hypotension, hypovolaemia, orthostatic hypotension, and syncope] was similar to placebo (Gibtulio 10 mg 0.5%, Gibtulio 25 mg 0.3% and placebo 0.3%). The effect of Gibtulio on urinary glucose excretion is associated with osmotic diuresis, which could affect hydration status of patients ≥75 years. In patients ≥75 years the frequency of volume depletion events was similar for Gibtulio 10 mg (2.3%) compared to placebo (2.1%), but it increased with Gibtulio 25 mg (4.4%).

Cardiovascular Safety: In a prospective, pre-specified meta-analysis of independently adjudicated cardiovascular events from 12 phase II and III clinical studies involving 10,036 patients with type 2 diabetes, Gibtulio did not increase cardiovascular risk.

In a randomized, placebo-controlled, active-comparator, crossover study of 30 healthy subjects no increase in QTc was observed with either 25 mg or 200 mg Gibtulio.