Sitagliptin and simvastatin

Uses

Primary hypercholesterolemia (type IIa and IIb) in patients who have not responded adequately to diet and other appropriate measures. Coronary heart disease and elevated plasma cholesterol level.

Monotherapy: Sitagliptin is used for an adjunct to diet and exercise to improve glycemic control in patients with type ll diabetes mellitus.

Combination with Metformin: Sitagliptin is used for patients with type 2 diabetes mellitus to improve glycemic control in combination with Metformin as initial therapy or when the single agent alone, with diet and exercise, does not provide adequate glycemic control.

Combination with a Sulfonylurea: Sitagliptin is used for patients with type ll diabetes mellitus to improve glycemic control in combination with a sulfonylurea when treatment with the single agent alone, with diet and exercise, does not provide adequate glycemic control.

Combination with a Thiazolidinediones: Sitagliptin is used for patients with type ll diabetes mellitus to improve glycemic control in combination with a thiazolidinedi- one when treatment with the single agent alone, with diet and exercise, does not provide adequate glycemic control.

Combination with Metformin and a Sulfonylurea: Sitagliptin is used for patients with type ll diabetes mellitus to improve glycemic control in combination with Metformin and a sulfonylurea when dual therapy with these agents, with diet and exercise, does not provide adequate glycemic control.

Sitagliptin and simvastatin is also used to associated treatment for these conditions: Cardiovascular Events, Diabetes Mellitus, Heterozygous Familial Hypercholesterolemia, High Cholesterol, Homozygous Familial Hypercholesterolemia, Mixed Hyperlipidemia, History of coronary heart disease cardiovascular event, History of stroke or other cerebrovascular disease cardiovascular eventType 2 Diabetes Mellitus

How Sitagliptin and simvastatin works

Simvastatin is a prodrug in which the 6-membered lactone ring of simvastatin is hydrolyzed in vivo to generate the beta,delta-dihydroxy acid, an active metabolite structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Simvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Simvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL.

At therapeutic doses, the HMG-CoA enzyme is not completely blocked by simvastatin activity, thereby allowing biologically necessary amounts of mevalonate to remain available. As mevalonate is an early step in the biosynthetic pathway for cholesterol, therapy with simvastatin would also not be expected to cause any accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolized readily back to acetyl-CoA, which participates in many biosynthetic processes in the body.

In vitro and in vivo animal studies also demonstrate that simvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response.

Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation.

Inhibition of DPP-4 by sitagliptin slows DPP-4 mediated inactivation of incretins like GLP-1 and GIP. Incretins are released throughout the day and upregulated in response to meals as part of glucose homeostasis. Reduced inhibition of incretins increase insulin synthesis and decrease glucagon release in a manner dependant on glucose concentrations. These effects lead to an overall increase in blood glucose control which is demonstrated by reduced glycosylated hemoglobin (HbA1c).

Dosage

Sitagliptin and simvastatin dosage

The patient should be placed on a standard cholesterol lowering diet before receiving Simvastatin and should continue on this during treatment with Simvastatin. The usual starting dose is 10 mg/day given as a single dose in the evening. Adjustment of dosage, if required, should be made at intervals of not less than four weeks, to a maximum of 40 mg daily given as a single dose in the evening. If LDL-cholesterol levels fall below 2 mmol/L or total plasma cholesterol levels fall below 3.5 mmol/L consideration should be given to reducing the dose of Simvastatin. In hypercholesterolemia, the recommended starting dose is 5-10 mg once a day in the evening and the recommended dosing range is 5-40 mg per day as a single dose in the evening. In patients with coronary heart disease and hypercholesterolemia, the starting dose should be 20 mg once a day in the evening. Because Simvastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with renal insufficiency. Safety and effectiveness in children and adolescents have not been established.

The recommended dose of Sitagliptin is 100 mg once daily as monotherapy or as combination therapy with Metformin, a sulfonylurea, a thiazolidinedione, or Metformin plus a sulfonylurea. Sitagliptin can be taken with or without food.

Elderly: No dosage adjustment is required based solely on age. The drug is excreted by the kidney. As elderly patients are more likely to have decreased renal function, caution should be taken in dose selection in the elderly.

Pediatric use: There is no data on use of Sitagliptin in patients younger than 18 years of age and therefore not recommended.

Side Effects

Simvastatin is generally well tolerated. Headache, fatigue, insomnia, gastrointestinal effects like nausea, constipation or diarrhoea, flatulence, dyspepsia, abdominal cramps and muscular effects like myalgia, myositis and myopathy have been reported. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been associated with Simvastatin therapy. Hepatitis, pancreatitis, rash, Angio-oedema have also been reported. No potentially life threatening effects have been reported.

The most common adverse reactions are; upper respiratory tract infection, nasopharyngitis and headache. Hypoglycemia may occur in patients treated with the combination of Sitagliptin and sulfonylurea and add-on to insulin.

Toxicity

Animal studies in pregnancy have shown no adverse effects on the mother or offspring at normal doses, however these results are not always applicable to humans. There is currently a voluntary registry of fetal exposure. Animal studies at 100 times the maximum recommended human dose resulted in an increase in rib malformations. Sitagliptin is excreted in the milk of rats but it is not known if it would also be expressed in human breast milk. Because many drugs are expressed in human breast milk, the risk and benefit of prescribing the medication must be considered. There is currently a lack of safety and effectiveness data in pediatric patients. No differences in safety and efficacy were observed in geriatric patients compared to younger patients, however caution should be used in this population as they are more likely to have reduced renal function. Sitagliptin has also been associated with a 34% relative risk increase for all cause infection. There was no significant difference in patient response across sex, age, race, ethnicity, and BMI.

Precaution

• If there is a history of liver disease
• Who take high alcohol
• Liver function test should be done before and during treatment
• If serum transaminase rises three times the upper limit of normal, treatment should be discontinued
• Avoid pregnancy during and for one month after treatment

Sitagliptin should not be used in patients with type l diabetes or for the treatment of diabetic ketoacidosis. Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD. Assessment of renal function is recommended prior to initiating Sitagliptin and periodically thereafter. When used with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia. There have been post marketing reports of serious allergic and hypersensitivity reactions in patients treated with Sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop Sitagliptin, assess for other potential causes, and institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. There have been no clinical studies establishing conclusive evidence of macrovascular risk.

Interaction

Digoxin: Concomitant administration of Simvastatin and Digoxin in normal volunteers resulted in a slight elevation (less than 0.3 µgm/ml) in drug concentrations in plasma compared to concomitant administration of placebo and Digoxin.

Coumarin derivatives: Slightly enhance the anticoagulant effect of Warfarin (mean changes in p rothrombin time less than two seconds) in normal volunteers maintained in a state of low therapeutic anticoagulation.

Others: In clinical studies, Simvastatin was used concomitantly with ACE inhibitors, beta-blockers, calcium channel blockers, diuretics and NSAIDs without evidence of clinically significant adverse interactions.

Co-administration of Digoxin and Sitagliptin may slightly increase the mean peak drug concentration of Digoxin. But no dosage adjustment of Digoxin or Sitagliptin is recommended.

Volume of Distribution

Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier.

198L.

Elimination Route

Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours post-dose. While the recommended therapeutic dose range is 10 to 40 mg/day, there was no substantial deviation from linearity of AUC with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal.

In a pharmacokinetic study of 17 healthy Chinese volunteers, the major PK parameters were as follows: Tmax 1.44 hours, Cmax 9.83 ug/L, t1/2 4.85 hours, and AUC 40.32ug·h/L.

Simvastatin undergoes extensive first-pass extraction in the liver, the target organ for the inhibition of HMG-CoA reductase and the primary site of action. This tissue selectivity (and consequent low systemic exposure) of orally administered simvastatin has been shown to be far greater than that observed when the drug is administered as the enzymatically active form, i.e. as the open hydroxyacid.

In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. However, because simvastatin undergoes extensive first-pass metabolism, the bioavailability of the drug in the systemic system is low. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reached the general circulation in the form of active inhibitors.

Genetic differences in the OATP1B1 (Organic-Anion-Transporting Polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact simvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) showed that simvastatin plasma concentrations were increased on average 3.2-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. The 521CC genotype is also associated with a marked increase in the risk of developing myopathy, likely secondary to increased systemic exposure. Other statin drugs impacted by this polymorphism include rosuvastatin, pitavastatin, atorvastatin, lovastatin, and pravastatin.

For patients known to have the above-mentioned c.521CC OATP1B1 genotype, a maximum daily dose of 20mg of simvastatin is recommended to avoid adverse effects from the increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis.

Evidence has also been obtained with other statins such as rosuvastatin that concurrent use of statins and inhibitors of Breast Cancer Resistance Protein (BCRP) such as elbasvir and grazoprevir increased the plasma concentration of these statins. Further evidence is needed, however a dose adjustment of simvastatin may be necessary. Other statin drugs impacted by this polymorphism include fluvastatin and atorvastatin.

Sitagliptin is 87% orally bioavailable and taking it with or without food does not affect its pharmacokinetics. Sitagliptin reaches maximum plasma concentration in 2 hours.

Half Life

4.85 hours

Approximately 12.4 hours. Other studies have reported a half life of approximately 11 hours.

Clearance

350mL/min.

Elimination Route

Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces.

Approximately 79% of sitagliptin is excreted in the urine as the unchanged parent compound. 87% of the dose is eliminated in the urine and 13% in the feces.

Pregnancy & Breastfeeding use

Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Pregnancy: Pregnancy Category B. Safety of Sitagliptin in pregnant women has not been established. Sitagliptin should be used during pregnancy only if the potential benefit justifies the potential risk of the fetus.

Nursing Mothers: It is not known whether Sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sitagliptin is administered to a nursing woman.

Contraindication

Simvastatin should not be used in-

• Active liver disease
• Pregnant and breast feeding mother
• Women of child bearing age unless they have been adequately protected by contraception
• Hypersensitivity to any component of the preparation
• Patients with the homozygous familial hypercholesterolemia who have a complete absence of LDL receptors

History of a serious hypersensitivity reaction to Sitagliptin, such as anaphylaxis or angioedema.

Special Warning

Renal Insufficiency-

• Mild renal insufficiency (creatinine clearance [CrCl] >50 mL/min, approximately corresponding to serum creatinine levels of >1.7 mg/dL in men and >1.5 mg/dL in women), no dosage adjustment for Sitagliptin is required.
• Moderate renal insufficiency (CrCl >30 to 1.7 to 1.5 to
• Severe renal insufficiency (CrCl 3.0 mg/dL in men and > 2.5 mg/dL in women) or with end -stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of Sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the timing of hemodialysis. Concomitant Use with a Sulfonylurea- When Sitagliptin is used in combination with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.

Hepatic Insufficiency: No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency. Sitagliptin has not been studied in patients with severe hepatic insufficiency.

Acute Overdose

There are no data available on overdose. No antidote is available. General measures should be adopted and liver function should be monitored.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.

Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.

Storage Condition

Store in a cool, dry place, Away from light keep out of reach of children.

Keep out of the reach of children. Store below 30° C. Keep in the original package in a cool & dry place in order to protect from light and moisture.

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