Azusa T

Indications

Azusa T is indicated for the treatment of hypertension

Adverse Effects

Azelnidipine The possible side effects of Azelnidipine include cardiac arrest, cardiac failure, hypotension, bradycardia, concomitant disease, cerebral haemorrhage, decreased heart rate, human herpesvirus infection, ascitis and prolonged electrocardiogram Telmisartan Common adverse effects reported with telmisartan are Upper respiratory tract infection, Back pain, Sinusitis, Diarrhea, Pharyngitis.

Drug Interactions

Azelnidipine: With Azoles: It is considered that these drugs inhibit CYP3A4 and reduce the clearance of this drug With HIV Protease Inhibitors: It is considered that these drugs inhibit CYP3A4 and reduce the clearance of this drug With other anti-hypertensives: The pharmacological action is enhanced by the combined use of antihypertensive agents having different action mechanisms: Excessive pressure reduction may occur. If necessary, reduce the dose of other antihypertensive agents or this drug With Simvastatin: It has been reported that the AUC of simvastatin increases 2.0-fold. If necessary, discontinue administration of this drug or simvastatin: Competitive inhibition of CYP3A4 by these agents is thought to reduce mutual clearance. Special attention should be paid to patients with renal dysfunction Telmisartan: Warfarin: Telmisartan administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio; Coadministration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19.Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19

Mechanism of Action

Azelnidipine: Azelnidipine exerts an antihypertensive effect by dilating blood vessels based on L-type Ca channel antagonism Telmisartan: Telmisartan is an orally active and specific angiotensin II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting Telmisartan does not show affinity for other receptors, including AT2 and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by telmisartan Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse effects In human, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours

Pharmacokinetics

The half life of Azelnidipine in Azusa T is 19-23 hours; half life of Telmisartan in Azusa T is 20 hours

Absorption, Distribution, Metabolism & Excretion

Azelnidipine Absorption Oral ingestion of azelnidipine demonstrates rapid and dose-dependent absorption. Route of Elimination In one study, following a single 4mg oral dose of 14C-labeled azelnidipine in humans, about 26% of the drug was thought to br excreted in the urine and 63% in the feces during the 1 week period post administration Volume of Distribution In a Chinese study examining the pharmacokinetics of the drug, the volume of distribution was found to be 1749 +/- 964. Metabolism/Metabolites Like most members of its class, azelnidipine primarily undergoes first-pass hepatic metabolism. Azelnidipine is metabolized by hepatic cytochrome P450 (CYP) 3A4 and has no active metabolite product. It may interact with other drugs or compounds that are substrates for this enzyme. Azelnidipine is lipophilic and has a potent affinity for membranes of vascular smooth muscle cells. Biological Half-Life 16 –28 hours Telmisartan: Absorption: Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for telmisartan is about 50 %. When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC0-∞) of telmisartan varies from approximately 6 % (40 mg dose) to approximately 19 % (160 mg dose). By 3 hours after administration, plasma concentrations are similar whether telmisartan is taken fasting or with food Distribution: Telmisartan is largely bound to plasma protein (>99.5 %), mainly albumin and alpha-1 acid glycoprotein. Biotransformation: Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate Elimination: Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of>20 hours. The maximum plasma concentration (Cmax) and, to a smaller extent, the area under the plasma concentration-time curve (AUC), increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan taken at the recommended dose

Drug Use in Pregnancy

Azelnidipine: Pregnant woman Do not administer to pregnant women or women who may be pregnant. Lactating women Consider continuing or discontinuing breastfeeding, taking into account the therapeutic benefits and benefits of breastfeeding. It has been reported in animal experiments that it is transferred into milk. Telmisartan: Pregnancy: There are no adequate data from the use of Telmisartan in pregnant women. Studies in animals have shown reproductive toxicity Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. While there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended Breast-feeding: Because no information is available regarding the use of Telmisartan during breast-feeding, Telmisartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant

Drug Use in Renal Impairment

Telmisartan: Renal Impairement:Renal Insufficiency: Renal excretion does not contribute to the clearance of telmisartan. Based on modest experience in patients with mild-to-moderate renal impairment (creatinine clearance of 30-80 mL/min, mean clearance approximately 50 mL/min), no dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration Azelnidipine: Patients with severe renal dysfunction Renal function may decline with blood pressure reduction

Drug Use in Hepatic Impairment

Telmisartan: Hepatic Insufficiency: In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% Azelnidipine: Patients with severe liver dysfunction No clinical trials have been conducted in patients with severe liver dysfunction.

Drug Use in Pediatric Population

Telmisartan:Pediatric: Telmisartan pharmacokinetics have not been investigated in patients <18 years of age. Azelnidipine: Children. No clinical trials have been conducted on children.

Drug Use in Geriatric Population

Telmisartan: Geriatric: The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years Azelnidipine: Elderly Start with 8 mg or even lower doses and administer with caution. Excessive pressure reduction is generally considered unfavorable. Cerebral infarction etc. may occur.