Actions of Olsertain ACTIVE in details
Pharmacology: Pharmacodynamics: Olsertain ACTIVE medoxomil doses of 2.5-40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of Olsertain ACTIVE medoxomil >40 mg giving >90% inhibition at 24 hrs.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of Olsertain ACTIVE medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to Olsertain ACTIVE medoxomil 80 mg had minimal influence on aldosterone levels and no effect on serum potassium.
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. Olsertain ACTIVE blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the angiotensin I receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
An angiotensin II receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olsertain ACTIVE has more than a 12,500-fold greater affinity for the Angiotensin I receptor than for the angiotensin II receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. Angiotensin-converting enzyme inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because Olsertain ACTIVE medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.
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 circulating angiotensin II levels do not overcome the effect of Olsertain ACTIVE on blood pressure.
Pharmacokinetics: Absorption: Olsertain ACTIVE medoxomil is rapidly and completely bioactivated by ester hydrolysis to Olsertain ACTIVE during absorption from the gastrointestinal tract.
The absolute bioavailability of Olsertain ACTIVE is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of Olsertain ACTIVE is reached after 1-2 hrs. Food does not affect the bioavailability of Olsertain ACTIVE.
Distribution: The volume of distribution of Olsertain ACTIVE is approximately 17 L. Olsertain ACTIVE is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein-binding is constant at plasma Olsertain ACTIVE concentrations well above the range achieved with recommended doses.
In rats, Olsertain ACTIVE crossed the blood-brain barrier poorly, if at all. Olsertain ACTIVE passed across the placental barrier in rats and was distributed to the fetus. Olsertain ACTIVE was distributed to milk at low levels in rats.
Metabolism and Excretion: Following the rapid and complete conversion of Olsertain ACTIVE medoxomil to Olsertain ACTIVE during absorption, there is virtually no further metabolism of Olsertain ACTIVE. Total plasma clearance of Olsertain ACTIVE is 1.3 L/hr, with a renal clearance of 0.6 L/hr. Approximately 35-50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.
Olsertain ACTIVE appears to be eliminated in a biphasic manner with a terminal elimination half-life (t½) of approximately 13 hrs. Olsertain ACTIVE shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of Olsertain ACTIVE are achieved within 3-5 days and no accumulation in plasma occurs with once-daily dosing.
Special Populations: Geriatric: The pharmacokinetics of Olsertain ACTIVE were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of Olsertain ACTIVE were similar in young adults and the elderly. Modest accumulation of Olsertain ACTIVE was observed in the elderly with repeated dosing; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR.
Pediatric: The pharmacokinetics of Olsertain ACTIVE were studied in pediatric hypertensive patients aged 1-16 years.
The clearance of Olsertain ACTIVE in pediatric patients was similar to that in adult patients when adjusted by the body weight.
Olsertain ACTIVE pharmacokinetics have not been investigated in pediatric patients <1 year.
Gender: Minor differences were observed in the pharmacokinetics of Olsertain ACTIVE in women compared to men. Area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) were 10-15% higher in women than in men.
Hepatic Insufficiency: Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.
Renal Insufficiency: In patients with renal insufficiency, serum concentrations of Olsertain ACTIVE were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment [creatinine clearance (CrCl) <20 mL/min]. The pharmacokinetics of Olsertain ACTIVE in patients undergoing hemodialysis has not been studied.
Drug Interactions: Bile Acid Sequestering Agent Colesevelam: Concomitant administration of Olsertain ACTIVE medoxomil 40 mg and colesevelam hydrochloride 3750 mg in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of Olsertain ACTIVE. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when Olsertain ACTIVE medoxomil was administered 4 hrs prior to colesevelam hydrochloride.
Toxicology: Preclinical Safety: Carcinogenesis, Mutagenesis, Impairment of Fertility: Olsertain ACTIVE medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two (2) carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of Olsertain ACTIVE medoxomil.
Both Olsertain ACTIVE medoxomil and Olsertain ACTIVE tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test.
However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olsertain ACTIVE medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (Olsertain ACTIVE not tested).
Fertility of rats was unaffected by administration of Olsertain ACTIVE medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.
Reproductive Toxicology Studies: No teratogenic effects were observed when Olsertain ACTIVE medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the MRHD of Olsertain ACTIVE medoxomil on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (½ the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day.
The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about 1/10 the MRHD of 40 mg/day.
How should I take Olsertain ACTIVE?
In addition to taking Olsertain ACTIVE, treatment for your high blood pressure may include weight control and a change in the foods you eat, especially foods high in sodium (salt). Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.
Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.
Remember that Olsertain ACTIVE will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You might have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease.
Olsertain ACTIVE may be taken with or without food.
If your child cannot swallow the tablets, your doctor may give him/her an oral liquid that is to be prepared by a pharmacist.
To use the oral liquid:
- Shake the oral liquid well before each use.
- Measure the medicine with a marked measuring spoon, oral syringe, or medicine cup. The average household teaspoon may not hold the right amount of liquid.
- Store the oral liquid in the refrigerator for up to 4 weeks. Throw away any unused medicine after 4 weeks.
If you are also using colesevelam (Welchol®), take it at least 4 hours after taking Olsertain ACTIVE®.
Dosing
The dose of Olsertain ACTIVE 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 Olsertain ACTIVE. 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 high blood pressure:
- Adults—At first, 20 milligrams (mg) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 40 mg once a day.
- Children 6 to 16 years of age weighing 35 kilograms (kg) or more—Dose is based on body weight and must be determined by your doctor. The dose is usually 20 to 40 mg once a day. If the child cannot swallow the tablets, an oral suspension is recommended.
- Children 6 to 16 years of age weighing at least 20 kilograms (kg) and less than 35 kg—Dose is based on body weight and must be determined by your doctor. The dose is usually 10 to 20 mg once a day. If the child cannot swallow the tablets, an oral suspension is recommended.
- Children 1 to 5 years of age—Use and dose must be determined by your doctor.
- Children younger than 1 year of age—Use is not recommended.
- For high blood pressure:
Missed Dose
If you miss a dose of Olsertain ACTIVE, 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.
Olsertain ACTIVE 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 Olsertain ACTIVE with or without food.
Your blood pressure will need to be checked often. Visit your doctor regularly.
Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low salt diet, or taking diuretics (water pills). Follow your doctor's instructions about the type and amount of liquids you should drink while taking Olsertain ACTIVE. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.
Keep using this medicine as directed, 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 at room temperature away from moisture and heat.
Olsertain ACTIVE 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. Olsertain ACTIVE blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
An AT2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olsertain ACTIVE has more than a 12,500-fold greater affinity 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 a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because Olsertain ACTIVE medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.
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 circulating angiotensin II levels do not overcome the effect of Olsertain ACTIVE on blood pressure.
Pharmacodynamics
Olsertain ACTIVE doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of Olsertain ACTIVE >40 mg giving >90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of Olsertain ACTIVE to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg Olsertain ACTIVE had minimal influence on aldosterone levels and no effect on serum potassium.
Pharmacokinetics
Absorption
Olsertain ACTIVE medoxomil is rapidly and completely bioactivated by ester hydrolysis to Olsertain ACTIVE during absorption from the gastrointestinal tract.
Olsertain ACTIVE tablets and the suspension formulation prepared from Olsertain ACTIVE tablets are bioequivalent.
The absolute bioavailability of Olsertain ACTIVE is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of Olsertain ACTIVE is reached after 1 to 2 hours. Food does not affect the bioavailability of Olsertain ACTIVE.
Distribution
The volume of distribution of Olsertain ACTIVE is approximately 17 L. Olsertain ACTIVE is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma Olsertain ACTIVE concentrations well above the range achieved with recommended doses.
In rats, Olsertain ACTIVE crossed the blood-brain barrier poorly, if at all. Olsertain ACTIVE passed across the placental barrier in rats and was distributed to the fetus. Olsertain ACTIVE was distributed to milk at low levels in rats.
Metabolism and Excretion
Following the rapid and complete conversion of Olsertain ACTIVE medoxomil to Olsertain ACTIVE during absorption, there is virtually no further metabolism of Olsertain ACTIVE. Total plasma clearance of Olsertain ACTIVE is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.
Olsertain ACTIVE appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olsertain ACTIVE shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of Olsertain ACTIVE are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing.
Geriatric
The pharmacokinetics of Olsertain ACTIVE were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of Olsertain ACTIVE were similar in young adults and the elderly. Modest accumulation of Olsertain ACTIVE was observed in the elderly with repeated dosing; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR.
Pediatric
The pharmacokinetics of Olsertain ACTIVE were studied in pediatric hypertensive patients aged 1 to16 years. The clearance of Olsertain ACTIVE in pediatric patients was similar to that in adult patients when adjusted by the body weight.
Olsertain ACTIVE pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.
Gender
Minor differences were observed in the pharmacokinetics of Olsertain ACTIVE in women compared to men. AUC and Cmax were 10-15% higher in women than in men.
Hepatic Insufficiency
Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.
Renal Insufficiency
In patients with renal insufficiency, serum concentrations of Olsertain ACTIVE were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of Olsertain ACTIVE in patients undergoing hemodialysis has not been studied.
Drug Interactions
Bile acid sequestering agent colesevelam
Concomitant administration of 40 mg Olsertain ACTIVE medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of Olsertain ACTIVE. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when Olsertain ACTIVE m edoxomil was administered 4 hours prior to colesevelam hydrochloride.
References
- NCIt. "Olmesartan: 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. "Olmesartan: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
