Actions of Friladar in details
Oral hypoglycemic agent.
Pharmacology: Mechanism of Action: The primary mechanism of action of Friladar appears to be dependent on stimulating the release of insulin from functioning pancreatic β-cells.
In addition, extra-pancreatic effects (eg, reduction of basal hepatic glucose production and increased peripheral tissue sensitivity to insulin and glucose uptake) may also play a role in the activity of Friladar.
However, as with other sulfonylureas, the mechanism by which Friladar lowers blood glucose during long-term administration has not been clearly established.
Pharmacokinetics: After oral administration, Friladar is completely absorbed from the GI tract. The oral bioavailabity is approximately 100%. Peak plasma concentrations occur in 2-3 hrs. More than 99% of the drug is bound to plasma proteins. Friladar is completely metabolized by oxidative biotransformation into 2 main metabolites, a hydroxy derivative and a carboxy derivative.
The elimination t½ after multiple doses is about 5-8 hrs. Approximately 60% of dose is eliminated in the urine and 40% in the feces.
Specific Populations: Renal Insufficiency: A single-dose clinical study of Friladar showed that Friladar serum levels decreased as renal function decreased. However, metabolites serum levels (mean AUC values) increased. The apparent terminal t½ for Friladar did not change, while the half-lives for metabolites increased as renal function decreased. Mean urinary excretion of metabolites as percent of dose, however, decreased.
How should I take Friladar?
Carefully follow the special meal plan your doctor gave you. This is a very important part of controlling your condition, and is necessary if the medicine is to work properly. Also, exercise regularly and test for sugar in your blood or urine as directed.
You should take Friladar with breakfast or the first main meal of the day.
Dosing
The dose of Friladar will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Friladar. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For oral dosage form (tablets):
- For type 2 diabetes:
- Adults—At first, 1 to 2 milligrams (mg) once a day. Your doctor may adjust your dose until your blood sugar is controlled. However, the dose is usually not more than 8 mg per day.
- Children—Use and dose must be determined by your doctor.
- For type 2 diabetes:
Missed Dose
If you miss a dose of Friladar, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Storage
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Friladar administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Friladar is usually taken once a day with breakfast or the first main meal of the day. Follow your doctor's instructions. Take Friladar with a full glass of water.
Know the signs of low blood sugar (hypoglycemia) and how to recognize them: headache, hunger, weakness, sweating, tremor, irritability, or trouble concentrating.
Always keep a source of sugar available in case you have symptoms of low blood sugar. Sugar sources include orange juice, glucose gel, candy, or milk. If you have severe hypoglycemia and cannot eat or drink, use an injection of glucagon. Your doctor can give you a prescription for a glucagon emergency injection kit and tell you how to give the injection.
Your dose needs may change if you are ill, if you have a fever or infection, or if you have surgery or a medical emergency.
Ask your doctor how to adjust your Friladar dose if needed. Do not change your medication dose or schedule without your doctor's advice.
Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office. Visit your doctor regularly.
Friladar is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.
Store at room temperature away from moisture and heat.
Friladar pharmacology
Mechanism of Action
Friladar primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.
Pharmacodynamics
In healthy subjects, the time to reach maximal effect (minimum blood glucose concentrations) was approximately 2–3 hours after single oral doses of Friladar. The effects of Friladar on HbA1c, fasting plasma glucose, and post-prandial glucose have been assessed in clinical trials.
Pharmacokinetics
Absorption: Studies with single oral doses of Friladar in healthy subjects and with multiple oral doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours post-dose. When Friladar was given with meals, the mean Cmax and AUC (area under the curve) were decreased by 8% and 9%, respectively.
Friladar does not accumulate in serum following multiple dosing. The pharmacokinetics of Friladar does not differ between healthy subjects and patients with type 2 diabetes. Clearance of Friladar after oral administration does not change over the 1 mg to 8 mg dose range, indicating linear pharmacokinetics.
In healthy subjects, the intra- and inter-individual variabilities of Friladar pharmacokinetic parameters were 15–23% and 24–29%, respectively.
Distribution: After intravenous dosing in healthy subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.
Metabolism: Friladar is completely metabolized by oxidative biotransformation after either an intravenous or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the biotransformation of Friladar to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M2 is inactive. In animals, M1 possesses about one-third of the pharmacological activity of Friladar, but it is unclear whether M1 results in clinically meaningful effects on blood glucose in humans.
Excretion: When 14C-Friladar was given orally to 3 healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days. M1 and M2 accounted for 80–90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces. M1 and M2 accounted for about 70% (ratio of M1 to M2 was 1:3) of the radioactivity recovered in feces. No parent drug was recovered from urine or feces. After intravenous dosing in patients, no significant biliary excretion of Friladar or its M1 metabolite was observed.
Geriatric Patients: A comparison of Friladar pharmacokinetics in patients with type 2 diabetes ≤65 years and those >65 years was evaluated in a multiple-dose study using Friladar 6 mg daily. There were no significant differences in Friladar pharmacokinetics between the two age groups. The mean AUC at steady state for the older patients was approximately 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was approximately 11% higher than that for the younger patients.
Gender: There were no differences between males and females in the pharmacokinetics of Friladar when adjustment was made for differences in body weight.
Race: No studies have been conducted to assess the effects of race on Friladar pharmacokinetics but in placebo-controlled trials of Friladar in patients with type 2 diabetes, the reduction in HbA1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).
Renal Impairment: A single-dose, open-label study Friladar 3 mg was administered to patients with mild, moderate and severe renal impairment as estimated by creatinine clearance (CLcr): Group I consisted of 5 patients with mild renal impairment (CLcr > 50 mL/min), Group II consisted of 3 patients with moderate renal impairment (CLcr = 20–50 mL/min) and Group III consisted of 7 patients with severe renal impairment (CLcr < 20 mL/min). Although, Friladar serum concentrations decreased with decreasing renal function, Group III had a 2.3-fold higher mean AUC for M1 and an 8.6-fold higher mean AUC for M2 compared to corresponding mean AUCs in Group I. The apparent terminal half-life (T1/2) for Friladar did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as a percentage of dose decreased from 44.4% for Group I to 21.9% for Group II and 9.3% for Group III.
Hepatic Impairment: It is unknown whether there is an effect of hepatic impairment on Friladar pharmacokinetics because the pharmacokinetics of Friladar has not been adequately evaluated in patients with hepatic impairment.
Obese Patients: The pharmacokinetics of Friladar and its metabolites were measured in a single-dose study involving 28 patients with type 2 diabetes who either had normal body weight or were morbidly obese. While the tmax, clearance, and volume of distribution of Friladar in the morbidly obese patients were similar to those in the normal weight group, the morbidly obese had lower Cmax and AUC than those of normal body weight. The mean Cmax, AUC0–24, AUC0–∞ values of Friladar in normal vs. morbidly obese patients were 547 ± 218 ng/mL vs. 410 ± 124 ng/mL, 3210 ± 1030 hours∙ng/mL vs. 2820 ± 1110 hours∙ng/mL and 4000 ± 1320 hours∙ng/mL vs. 3280 ± 1360 hours∙ng/mL, respectively.
Drug Interactions:
Aspirin: In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or aspirin 1 gram three times daily for a total treatment period of 5 days. On Day 4 of each study period, a single 1 mg dose of Friladar was administered. The Friladar doses were separated by a 14-day washout period. Co-administration of aspirin and Friladar resulted in a 34% decrease in the mean Friladar AUC and a 4% decrease in the mean Friladar Cmax.
Colesevelam: Concomitant administration of colesevelam and Friladar resulted in reductions in Friladar AUC0–∞ and Cmax of 18% and 8%, respectively. When Friladar was administered 4 hours prior to colesevelam, there was no significant change in Friladar AUC0–∞ or Cmax, -6% and 3%, respectively.
Cimetidine and Ranitidine: In a randomized, open-label, 3-way crossover study, healthy subjects received either a single 4 mg dose of Friladar alone, Friladar with ranitidine (150 mg twice daily for 4 days; Friladar was administered on Day 3), or Friladar with cimetidine (800 mg daily for 4 days; Friladar was administered on Day 3). Co-administration of cimetidine or ranitidine with a single 4 mg oral dose of Friladar did not significantly alter the absorption and disposition of Friladar.
Propranolol: In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or propranolol 40 mg three times daily for a total treatment period of 5 days. On Day 4 or each study period, a single 2 mg dose of Friladar was administered. The Friladar doses were separated by a 14-day washout period. Concomitant administration of propranolol and Friladar significantly increased Friladar Cmax, AUC, and T 1/2 by 23%, 22%, and 15%, respectively, and decreased Friladar CL/f by 18%. The recovery of M1 and M2 from urine was not changed.
Warfarin: In an open-label, two-way, crossover study, healthy subjects received 4 mg of Friladar daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting Friladar and on Day 4 of Friladar administration. The concomitant administration of Friladar did not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in warfarin plasma protein binding. Friladar resulted in a statistically significant decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during Friladar treatment were 3.3% and 9.9%, respectively, and are unlikely to be clinically relevant.
References
- DailyMed. "GLIMEPIRIDE; PIOGLITAZONE HYDROCHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Glimepiride: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Glimepiride: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
The results of a survey conducted on ndrugs.com for Friladar are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Friladar. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.User reports
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Information checked by Dr. Sachin Kumar, MD Pharmacology
