Actions of Telmipharm in details
Pharmacology: Telmipharm is an orally effective and specific angiotensin-II receptor (type AT1) antagonist. Telmipharm 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. Telmipharm does not exhibit any partial agonist activity at the AT1 receptor. Telmipharm selectively binds the AT1 receptor. The binding is long lasting.
Telmipharm 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 Telmipharm. Plasma aldosterone levels are decreased by Telmipharm. Telmipharm does not inhibit human plasma renin or block ion channels. Telmipharm 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 man, an 80 mg dose of Telmipharm 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.
Treatment of Essential Hypertension: After the first dose of Telmipharm, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 weeks after the start of treatment and is sustained during long-term therapy.
The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of Telmipharm 40 and 80 mg in placebo-controlled clinical studies.
There is an apparent trend to a dose relationship to a time to recovery of baseline systolic blood pressure (SBP). In this respect, data concerning diastolic blood pressure (DBP) are inconsistent.
In patients with hypertension, Telmipharm reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of Telmipharm has been compared to antihypertensive drugs such as amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan, lisinopril, ramipril and valsartan.
Upon abrupt cessation of treatment with Telmipharm, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.
Telmipharm treatment has been shown in clinical trials to be associated with statistically significant reductions in Left Ventricular Mass and Left Ventricular Mass Index in patients with hypertension and Left Ventricular Hypertrophy.
Telmipharm treatment has been shown in clinical trials (including comparators like losartan, ramipril and valsartan) to be associated with statistically significant reductions in proteinuria (including microalbuminuria and macroalbuminuria) in patients with hypertension and diabetic nephropathy.
The incidence of dry cough was significantly lower in patients treated with Telmipharm than in those given with angiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.
Cardiovascular Risk Reduction: ONTARGET (ONgoing Telmipharm Alone and in combination with Ramipril Global Endpoint Trial) compared the effects of Telmipharm, ramipril and the combination of Telmipharm and ramipril on cardiovascular outcomes in 25,620 patients aged 55 years or older with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes mellitus accompanied by evidence of end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which represents a broad cross-section of cardiovascular high risk patients.
Patients were randomized to one of the three following treatment groups: Telmipharm 80 mg (n=8,542), ramipril 10 mg (n=8,576), or the combination of Telmipharm 80 mg plus ramipril 10 mg (n=8,502), and followed for a mean observation time of 4.5 years. The population studied was 73% male, 74% Caucasian, 14% Asian and 43% were 65 years of age or older. Hypertension was present in nearly 83% of randomized patients: 69% of patients had a history of hypertension at randomization and an additional 14% had actual blood pressure readings above 140/90 mmHg. At baseline, the total percentage of patients with a medical history of diabetes was 38% and an additional 3% presented with elevated fasting plasma glucose levels. Baseline therapy included acetylsalicylic acid (76%), statins (62%), beta-blockers (57%), calcium-channel blockers (34%), nitrates (29%) and diuretics (28%).
The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure.
Adherence to treatment was better for Telmipharm than for ramipril or the combination of Telmipharm and ramipril, although the study population had been pre-screened for tolerance to treatment with an ACE-inhibitor. The analysis of adverse events leading to permanent treatment discontinuation and of serious adverse events showed that cough and angioedema were less frequently reported in patients treated with Telmipharm than in patients treated with ramipril, whereas hypotension was more frequently reported with Telmipharm.
Telmipharm had similar efficacy to ramipril in reducing the primary endpoint. The incidence of the primary endpoint was similar in the Telmipharm (16.7%), ramipril (16.5%) and Telmipharm plus ramipril combination (16.3%) arms. The hazard ratio for Telmipharm vs. ramipril was 1.01 [97.5% CI 0.93-1.10, p (non-inferiority)=0.0019]. The treatment effect was found to persist following corrections for differences in systolic blood pressure at baseline and over time. There was no difference in the primary endpoint based on age, gender, race, baseline therapies or underlying disease.
Telmipharm was also found to be similarly effective to ramipril in several pre-specified secondary endpoints, including a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, the primary endpoint in the reference study HOPE (The Heart Outcomes Prevention Evaluation Study), which had investigated the effect of ramipril vs. placebo. The hazard ratio of Telmipharm vs. ramipril for this endpoint in ONTARGET was 0.99 [97.5% CI 0.90-1.08, p (non-inferiority)=0.0004].
Combining Telmipharm with ramipril did not add further benefit over ramipril or Telmipharm alone. In addition, there was a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in the combination arm. Therefore, the use of a combination of Telmipharm and ramipril is not recommended in this population.
Pharmacokinetics: Absorption of Telmipharm is rapid although the amount absorbed varies. The mean absolute bioavailability for Telmipharm is about 50%.
When Telmipharm is taken with food, the reduction in the area under the plasma concentration-time curve (AUC) of Telmipharm varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). By 3 hours after administration, plasma concentrations are similar whether Telmipharm is taken fasting or with food.
The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy.
Gender differences in plasma concentrations were observed, Cmax and AUC being approximately 3- and 2-fold higher, respectively, in females compared to males without relevant influence on efficacy.
Telmipharm is largely bound to plasma protein (>99.5%), mainly albumin and alpha-1 acid glycoprotein. The mean steady-state apparent volume of distribution (Vss) is approximately 500 L.
Telmipharm is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.
Telmipharm 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, area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There is no evidence of clinically relevant accumulation of Telmipharm.
After oral (and intravenous) administration, Telmipharm is nearly exclusively excreted with the faeces, exclusively as unchanged compound. Cumulative urinary excretion is <2% of dose. Total plasma clearance (ClTot) is high (approximately 900 mL/min) compared with hepatic blood flow (about 1,500 mL/min).
Elderly Patients: The pharmacokinetics of Telmipharm do not differ between younger and elderly patients.
Patients with Renal Impairment: Lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmipharm is highly bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.
Patients with Hepatic Impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%. The elimination half-life is not changed in patients with hepatic impairment.
How should I take Telmipharm?
Take Telmipharm exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.
You may take Telmipharm with or without food.
Do not crush, chew, or break a Telmipharm tablet. Swallow the tablet whole. Keep each tablet in its blister pack until you are ready to take it. Tear or cut the blister apart from the rest of the package and peel back the paper liner. Push the tablet through the foil to remove it.
It may take 2 to 4 weeks before your symptoms improve. Keep using the medicine as directed and tell your doctor if your symptoms do not improve.
Your blood pressure will need to be checked often.
You may have very low blood pressure while taking Telmipharm. Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual.
If you are being treated for high blood pressure, keep using this medicine even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
Store Telmipharm tablets in their original package at room temperature, away from moisture and heat.
Telmipharm 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.
Your doctor may occasionally change your dose to make sure you get the best results
You may take Telmipharm with or without food.
Your blood pressure will need to be checked often. Visit your doctor regularly.
It may take 2 to 4 weeks of using this medicine before your blood pressure is under control. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 4 weeks of treatment.
If you are being treated for high blood pressure, keep using this medication even if you feel fine. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
Store at room temperature away from moisture and heat.
Telmipharm pharmacology
Mechanism of Action
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmipharm blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmipharm has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because Telmipharm does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmipharm does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of Telmipharm on blood pressure.
Pharmacodynamics
In normal volunteers, a dose of Telmipharm 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.
Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose-dependent manner after single administration of Telmipharm to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg Telmipharm to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid).
In 30 hypertensive patients with normal renal function treated for 8 weeks with Telmipharm 80 mg or Telmipharm 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate, filtration fraction, renovascular resistance, or creatinine clearance.
Pharmacokinetics
Following oral administration, peak concentrations (Cmax) of Telmipharm are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of Telmipharm, with a reduction in the area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. The absolute bioavailability of Telmipharm is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered Telmipharm are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses. Telmipharm shows bi-exponential decay kinetics with a terminal elimination half life of approximately 24 hours. Trough plasma concentrations of Telmipharm with once daily dosing are about 10% to 25% of peak plasma concentrations. Telmipharm has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.
Distribution
Telmipharm is highly bound to plasma proteins (>99.5%), mainly albumin and α1 - acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for Telmipharm is approximately 500 liters indicating additional tissue binding.
Metabolism and Elimination
Following either intravenous or oral administration of 14C-labeled Telmipharm, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).
Telmipharm is metabolized by conjugation to form a pharmacologically inactive acyl glucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of Telmipharm.
Total plasma clearance of Telmipharm is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.
Specific Populations
Renal Insufficiency
No dosage adjustment is necessary in patients with decreased renal function. Telmipharm is not removed from blood by hemofiltration.
Hepatic Insufficiency
In patients with hepatic insufficiency, plasma concentrations of Telmipharm are increased, and absolute bioavailability approaches 100%.
Gender
Plasma concentrations of Telmipharm are generally 2 to 3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary.
Geriatric Patients
The pharmacokinetics of Telmipharm do not differ between the elderly and those younger than 65 years.
Pediatric Patients
Telmipharm pharmacokinetics have not been investigated in patients <18 years of age.
References
- DailyMed. "AMLODIPINE BESYLATE; TELMISARTAN: 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. "Telmisartan: 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. "Telmisartan: 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 Telmipharm 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 Telmipharm. 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
Consumer reported administration
No survey data has been collected yetConsumer reviews
There are no reviews yet. Be the first to write one! |
Information checked by Dr. Sachin Kumar, MD Pharmacology
