CLINICAL PHARMACOLOGY CARDS

 

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Mechanism of Action

 

Orally active chelator that is selective for iron (as Fe3+) for the treatment of chronic iron overload due to blood transfusions.
Pharmacodynamics (PD)

 

 

 

 

Deferasirox (10, 20,and 40 mg per kg per day) was able to induce a mean net iron excretion (0.119, 0.329,and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1 to 0.5 mg per kg per day). Iron excretion was predominantly fecal.

The effect of 20 and 40 mg per kg per day of deferasirox (tablets for oral suspension) as single dose showed no evidence of prolongation of the QTc interval.

Pharmacokinetics (PK)

 

 

 

 

 

 

 

 

 

 

 

 

Linear PK with mean elimination half-life ranged from 8 to 16 hours and mean steady state volume of distribution was of 14.37 L. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension was 70%. The bioavailability of JADENU was 36% greater than with deferasirox tablets for oral suspension.

AUC and Cmax were slightly decreased after a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and Cmax were increased by 18% and 29%, respectively. It is recommended that JADENU should be taken on an empty stomach or with a light meal.

Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.

Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin.

Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose).

Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3.

PK-PD Analysis Not reported
Population PK Not reported
Special Populations

 

 

 

 

Compared to patients with myelodysplastic syndrome (MDS) and CLCr greater than 60 mL/min, patients with MDS and CLCr 40 to 60 mL/min had approximately 50% higher mean deferasirox trough plasma concentrations.

In children less than 6 years of age, systemic exposure was about 50% lower than in adults, However, the safety and efficacy of deferasirox in pediatric patients was similar to that of adult patients.

Drug Interactions

 

 

 

 

Deferasirox may induce CYP3A4 and inhibit CYP2C8 and CYP1A2.

The concomitant use of JADENU with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in JADENU efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with JADENU due to a possible decrease in deferasirox concentration.

Source https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/jadenu.pdf


 

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Mechanism of Action

 

 

 

 

 

 

SYNJARDY combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a member of the biguanide class.

Empagliflozin, by inhibiting SGLT2, reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacodynamics (PD)

 

 

 

 

 

 

In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of empagliflozin and was maintained at the end of a 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily.

In a 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of empagliflozin 25 mg once daily treatment.

No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

Pharmacokinetics (PK)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SYNJARDY (empagliflozin/metformin hydrochloride) 5 mg/500 mg, 5 mg/1000 mg, 12.5 mg/500 mg, and 12.5 mg/1000 mg combination tablets are bioequivalent to coadministration of corresponding doses of empagliflozin and metformin as individual tablets.

Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.

There is a lack of dose proportionality with increasing Metformin doses, which is due to decreased absorption rather than an alteration in elimination. Plasma and blood elimination half-lives of Metformin are approximately 6.2 and 17.6 hours, respectively. The apparent volume of distribution of metformin following single oral dose of immediate-release metformin hydrochloride tablets 850 mg averaged 654±358 L.

Food has no clinically relevant effect on AUC or Cmax of empagliflozin or metformin.

Empagliflozin partitioned approximately 36.8% to red blood cell. Its plasma protein binding was 86.2%. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas (SUs), which are more than 90% protein bound.

Systemic exposure of each of 3 glucuronide conjugate metabolites of empagliflozin was less than 10% of total drug-related material.

Metformin excretes as unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.

The majority of drug-related radioactivity recovered in feces was unchanged empagliflozin and approximately half of drug-related radioactivity excreted in urine was unchanged empagliflozin.

Renal clearance of metformin is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. The change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

PK-PD Analysis Not reported
Population PK

 

 

 

The apparent steady-state volume of distribution of empagliflozin was estimated to be 73.8 L. The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis.

Body mass index, gender and race do not have a clinically meaningful effect on pharmacokinetics of empagliflozin.

Special Populations

 

 

 

 

 

Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin

In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively.

In healthy elderly subjects, the total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased.

Drug Interactions

 

 

 

 

PK drug interaction studies with SYNJARDY have not been performed; however, such studies have been conducted with the individual components empagliflozin and metformin.  No dose adjustment of empagliflozin is recommended when coadministered with commonly prescribed medicinal products based on results of the described PK studies.

Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin.

Source http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206111lbl.pdf

 

 

 

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