Amlodipine + Telmisartan

Amlodipine + Telmisartan is an antihypertensive agent belonging to the "Calcium Channel Blocker class " and " Angiotensin II Receptor Blocker class."

Amlodipine + Telmisartan is approved for treating hypertension (high blood pressure) in adults. This drug combination minimizes the risk of cardiovascular events by relaxing blood vessels and lowering the workload on the heart.

Amlodipine is absorbed orally, with peak plasma levels achieved in 6-12 hours. Telmisartan is absorbed more gradually, reaching its peak levels after 0.5 to 1 hour. Both medications are metabolized by the liver, with Telmisartan mainly excreted in faeces (biliary excretion) and Amlodipine primarily removed unchanged in urine.

The common side effects of Amlodipine + Telmisartan include oedema (swelling), hypotension (low blood pressure), pain in the back, and dizziness.

Amlodipine + Telmisartan is available as a tablet for convenient administration.

Amlodipine + Telmisartan is available in the United States, Canada, the United Kingdom, India and Australia.

Amlodipine + Telmisartan is an antihypertensive agent belonging to the Calcium Channel Blocker class and Angiotensin II Receptor Blocker class.

Amlodipine: Amlodipine primarily affects the smooth muscle of the arteries, lowering peripheral vascular resistance by preventing calcium ion inflow. According to experimental data, Amlodipine interacts with specific membrane binding sites. It mainly exerts its therapeutic effects by dilating peripheral arterioles, which lowers cardiac workload and oxygen consumption, and by promoting coronary artery dilation, which improves oxygen supply. It is beneficial in conditions like variant angina and mitigates coronary vasoconstriction. These two distinct mechanisms prove Amlodipine's effectiveness in treating angina and hypertension.

The Onset of action of Amlodipine is not clinically established.

The Duration of Action for Amlodipine in the body is approximately 24 hours.

The Tmax was found within 6-12 hours following the administration of Amlodipine.

Clearance: 25 L/hr

Telmisartan: Telmisartan selectively prevents angiotensin II from binding to the AT1 receptor in a variety of tissues, including as the vascular smooth muscle and the adrenal gland, hence preventing angiotensin II's vasoconstrictor and aldosterone-secreting effects. Limiting the effects of angiotensin II lowers systemic vascular resistance since it is a vasoconstrictor that induces aldosterone production and release.

The time taken for Telmisartan to show its effect must be clinically established.

Telmisartan may remain in your body for approximately 1-2 days.

Clearance: 800 mL/min

The Tmax was found within 0.5-1 hours following the administration of Telmisartan, and the Cmax was about 522.29 ng/mL.

Synergistic Benefits: Amlodipine + Telmisartan combines the benefits of an angiotensin II receptor blocker (Telmisartan) with a calcium channel blocker (Amlodipine) to successfully treat hypertension and associated cardiovascular problems. In contrast to Telmisartan, which expands blood vessels by preventing the effects of hormones constricting them, Amlodipine relaxes blood vessels, lowering peripheral vascular resistance. This combined effect reduces the risk of coronary artery disease, stroke, and heart failure by simultaneously lowering blood pressure and relieving the strain on the heart. Additionally, the combination of medicines protects general cardiovascular health by enhancing renal health and reducing the risk of incidents like strokes and heart attacks.

When one medication fails to regulate your blood pressure, these medications are combined.

Data Onset of action of Amlodipine + Telmisartan is shown within a few hours post-administration.

Data duration of action of Amlodipine + Telmisartan can last up to 24 hours.

The Data of Tmax of Amlodipine + Telmisartan is within 1 to 6 hours following oral administration.

The Data of Cmax of Amlodipine + Telmisartan needs to be established.

Amlodipine + Telmisartan is available in tablets.

Tablets: To be swallowed whole with water/liquid.

Take the medication by mouth once daily, generally with or without a meal, as recommended by the physician.

Hypertension is treated with the drug combination of Amlodipine and Telmisartan. Strokes, heart attacks, and renal issues can all be prevented by lowering excessive blood pressure. Amlodipine + Telmisartan acts as a calcium channel and angiotensin receptor blocker (ARB). They both work distinctly to relax the blood arteries and promote blood flow.

Amlodipine + Telmisartan is an antihypertensive agent belonging to the Calcium Channel Blocker class and Angiotensin II Receptor Blocker class.

Amlodipine: It prevents calcium ions from entering "slow channels" or particular voltage-sensitive regions of the myocardium and vascular smooth muscle during depolarization, resulting in relaxation of the latter and coronary vasodilation; it also increases myocardial oxygen delivery in people with vasospastic angina. Amlodipine directly affects vascular smooth muscle to cause peripheral arterial vasodilation, which lowers blood pressure and peripheral vascular resistance.

Telmisartan: Telmisartan helps to reduce high blood pressure or hypertension by relaxing blood vessels to improve blood flow.

The Amlodipine + Telmisartan combination has beneficial effects on hypertension by effectively lowering blood pressure through distinct mechanisms of action.They promote adequate blood circulation and relax blood vessels, eventually reducing the heart's burden. In addition to lowering the risk of cardiovascular events like heart attacks and strokes, this also helps prevent heart failure. It can also prevent renal disease from progressing, especially in situations when hypertension is present. For best results, this combination demands strict attention to the established routine. Its benefits might be experienced later, but over time, it works to maintain general well-being.

Amlodipine + Telmisartan is approved for use in the following clinical indications:

• Amlodipine + Telmisartan is indicated for managing high blood pressure, helping to lower and maintain blood pressure within a healthy range.
• This combination therapy might help to reduce the risk of cardiovascular events, including strokes and heart attacks, in patients with hypertension and other cardiovascular risk factors.
• Amlodipine + Telmisartan can slow the progression of kidney disease, particularly in individuals with hypertension-related kidney problems.

Orally: Amlodipine + Telmisartan is available as a tablet that can be taken orally. Amlodipine + Telmisartan should be taken either on an empty stomach or along with food. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Hypertension

Initiate with 40 mg/5 mg or 80 mg/5 mg orally qDay, OR

Replace separately for individually titrated components

After at least two weeks, the dose may increase; the maximum dosage is 80 mg/10 mg daily.

Telmisartan dosage range: 20–80 mg/2.5–10 mg amlodipine orally qDay

It may be used together with other antihypertensive medications.

For people above 75, starting the therapy is not advised.

Begin with a lower dose of 2.5 mg amlodipine and increase the amount slowly.

Amlodipine + Telmisartan is available in the form of Oral tablets.

Amlodipine + Telmisartan should be used in treating hypertension, along with appropriate dietary restrictions.

While taking this combination, it is advised to maintain a rich, balanced diet low in saturated fats and cholesterol and consume plenty of vegetables, whole grains, fruits, and lean proteins. Avoid excessive consumption of grapefruit, grapefruit juice, and food rich in potassium, such as bananas, nuts, sweet potatoes or alcohol, as it may interact with the medication.

The dietary restriction should be individualized as per patient requirements.

Amlodipine + Telmisartan may be contraindicated in patients with the following conditions:-

• Hypersensitivity
• Pregnancy
• Co-administer aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min)
• Severe Renal impairment
• History of Angioedema
• Hypotension
• Severe Liver Impairment

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• It might result in hypotension, especially if the volume or salt levels are low (fix before starting)
• Syncope or symptomatic hypotension may happen.
• Patients who have significant renal or hepatic impairment should be titrated cautiously.
• Serum creatinine or BUN levels can increase in patients with renal artery stenosis.
• Monitor acute hyperkalemia
• Be cautious in case of hypertrophic cardiomyopathy, severe aortic stenosis (Amlodipine), liver disease, renal artery stenosis, or any other conditions listed above.
• In contrast to monotherapy, dual blockage of the renin-angiotensin system with ARBs, ACE inhibitors, or aliskiren is linked to an increased risk of hyperkalemia, hypotension, and abnormalities in renal function, including acute renal failure.
• Monitor for deteriorating heart failure, which might cause oliguria or progressive azotemia.
• Patients with severe obstructive CAD who begin calcium channel blockers run the risk of MI or have worsening angina.

It is unsafe to consume alcohol with Amlodipine + Telmisartan

There is no sufficient scientific evidence traceable regarding the use and safety of Amlodipine + Telmisartan for breastfeeding populations.

Unsafe to use during pregnancy.

Avoid or minimize the consumption of grapefruit or grapefruit juice. Caution should be taken while consuming potassium-rich food, such as bananas, nuts, and sweet potatoes, as it can lead to hypercalcemia.

The adverse reactions related to Amlodipine + Telmisartan can be categorized as

Common: Peripheral edema

Less Common: Dizziness, orthostatic hypotension, syncope and pain in the back.

Rare: Severe allergic reactions

Reports on Postmarketing

The most often reported symptoms include upper respiratory infections, headaches, asthenia, coughing, nausea, weariness, hypoglycemia (in diabetic individuals), and angioedema (which can be deadly). Other common symptoms include gynecomastia, jaundice, and elevated liver enzymes.

The clinically relevant drug interactions of Amlodipine and Telmisartan are briefly summarized here.

• CYP3A Inhibitors: Amlodipine's systemic exposure increases when it is administered concurrently with CYP3A inhibitors, both mild and potent, and may necessitate dosage reduction. When using Amlodipine with CYP3A inhibitors, monitor for signs of hypotension and oedema to evaluate whether a dosage change is necessary.
• Sildenafil: Monitor closely for hypotension when sildenafil is co-administered with Amlodipine.
• Lithium: When given concurrently with angiotensin II receptor antagonists like Telmisartan, lithium has been shown to cause reversible elevations in blood lithium concentrations and toxicity. As a result, while using lithium concurrently, investigate serum lithium levels.
• Simvastatin: Co-administration of simvastatin with Amlodipine raises the systemic exposure of simvastatin. Limit the simvastatin dose in patients on Amlodipine to 20 mg daily.
• Diuretics: Hyperkalemia may occur with concomitant use of potassium-sparing diuretics and Telmisartan, which requires periodic electrolyte monitoring, particularly in patients with increased risk of hyperkalemia—potassium-sparing diuretics such as Amiloride, Eplerenone, Spironolactone, Triamterene.
• Non-steroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors (selective COX-2 inhibitors): Co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including Telmisartan, may worsen renal function in patients who are elderly, volume-depleted (including those on diuretic therapy), or with weak renal function. This could include acute renal failure. Usually, these effects are reversible. Patients using telmisartan and NSAIDs should have their renal function routinely checked.

• Sleepiness
• swollen ankles
• Headache
• (Feeling of warmth in the ears, neck, face, and trunk) Flushing
• Dizziness
• Tiredness
• Palpitations
• stomach ache
• Increased potassium level in the blood

Amlodipine + Telmisartan should be prudent in the following group of special populations

• Pregnancy:

Fetal/ Neonatal adverse reactions

Amlodipine: Pregnancy Category C

There haven't been any controlled studies conducted on pregnant women. Amlodipine should only be used during pregnancy if the benefits exceed the hazards to the developing foetus. Amlodipine maleate was given orally to pregnant rats and rabbits during key organ development periods at doses up to 10 mg amlodipine/kg/day (8 times and 23 times the maximum recommended human dose of 10 mg on a mg/m2 basis, respectively), and no teratogenicity or other embryo/fetal toxicity was found. The litter size significantly decreased by nearly 50% during mating and gestation in rats receiving the equivalent of 10 mg of amlodipine/kg/day for 14 days before mating, whereas intrauterine mortality dramatically increased (about 5-fold). Additionally, the rats' gestation and labour times were prolonged by this dosage.

Telmisartan: Pregnancy Categories C (first trimester) and D (second and third trimesters)

When used during the second or third trimester of pregnancy, Telmisartan, like other drugs that affect the renin-angiotensin system, can result in morbidity and death for the foetus and the newborn. When given to a pregnant woman, Telmisartan has the potential to harm the foetus, causing impairment of foetal renal function and production of oligohydramnios that can lead to skeletal malformations.

Due to the high potential risk to the foetus, avoid the Amlodipine + Telmisartan combination when pregnant. If pregnancy is detected, stop immediately and control hypertension according to pregnancy recommendations. Renin-angiotensin system medications in later stages of pregnancy might affect foetal renal function, raising hazards. Hypotension, neonatal skull hypoplasia, anuria, and renal failure, which might result in oligohydramnios, are just a few of the adverse outcomes. Additionally, this disorder may result in craniofacial deformities, undeveloped lungs, and foetal limb contractures. When using this drug while expecting or planning a pregnancy, use caution and consult a physician.

When using this drug while expecting or planning a pregnancy, use caution and consult a physician.

• Lactating Mothers

Minimal is known about the prevalence of these medicines in human milk and how they affect newborns. Amlodipine and Telmisartan may or may not be detected in animal and human milk, respectively. It is not advised to breastfeed while taking this medication combination since there might be severe side effects in breastfed infants.

Data

From 4 to 8 hours after injection, telmisartan concentrations were 1.5 to 2 times higher in lactating rats' milk than they were in their plasma.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have not been established.

Neonates with a history of in-utero drug exposure should be cautiously monitored for hypotension, oliguria, and Hyperkalemia.

• Geriatric Use

Geriatric people should have their use of Amlodipine +Telmisartan closely monitored. Elderly people may be more vulnerable to adverse drug reactions and drug interactions. It is essential to closely monitor liver and kidney function and any possible medication interactions. Depending on the individual's medical situation and drug regimen, dosage modifications may be required. It's crucial to monitor patients and consult with medical professionals regularly.

Dosage Adjustment in Kidney Impairment Patient

Renal impairment

Mild (CrCl 60 to 90 mL/min) to moderate (CrCl 30 to 60 mL/min): Specific dosage adjustments may not be necessary.

Severe (CrCl ≤30 mL/min): Administer slowly or not recommended.

Hemodialysis patients are more likely to have hypotension

Dosage Adjustment in Hepatic Impairment Patient

Hepatic impairment

Initiate with a lower dose of 2.5 mg amlodipine and increase the amount gradually. It is not advised for hepatically impaired individuals to start their treatment with telmisartan and amlodipine tablets since the lowest effective dose is 40/5 mg.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Amlodipine + Telmisartan. Overconsumption of Amlodipine + Telmisartan could lead to symptoms such as severe hypotension (low blood pressure) and electrolyte imbalances.

There is no specific antidote or treatment for excessive intake of Amlodipine + Telmisartan. However, immediate medical attention is essential.

Amlodipine + Telmisartan should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Management typically involves supportive measures and symptomatic treatment. Supportive therapy should be given, addressing any symptoms that persist or worsen. Activated charcoal may also be considered if the overdose is detected shortly after ingestion to reduce absorption. Monitoring the patient's vital signs and correcting any electrolyte imbalances, especially hyperkalemia (high potassium levels), is crucial. In severe cases, gastric lavage may be performed if ingestion occurs within the previous hour. Physical treatment might be added if necessary.

Pharmacodynamic of Amlodipine + Telmisartan

Amlodipine: Amlodipine binds to cell membranes with a high affinity and inhibits specific membrane calcium channels to modulate calcium influx. Long-acting effects and a less frequent dose schedule are made possible by this medication's unique binding qualities.

Telmisartan: Telmisartan is a nonpeptide, orally active angiotensin II antagonist that targets the AT1 receptor subtype alone. The angiotensin II receptor blockers (ARBs) currently on the market have the lowest affinity for the AT2 receptor and the highest affinity for the AT1 receptor. Telmisartan also has the potential to be an agonist for PPAR. This nuclear receptor controls the transcription of genes related to lipid and glucose metabolism and anti-inflammatory responses. Clinical studies are being conducted now to examine this possibility. ACE (angiotensin-converting enzyme) converts angiotensin I to angiotensin II, which is a crucial part of the renin-angiotensin system and is mainly responsible for vasoconstriction, aldosterone release, cardiac stimulation, and renal sodium chloride reabsorption. Telmisartan works by preventing the aldosterone-releasing and vasoconstrictive effects of angiotensin II.

Pharmacokinetics of Amlodipine + Telmisartan

Absorption:

Amlodipine: Amlodipine is slowly and almost entirely absorbed from the digestive tract. Peak plasma concentrations are reached 6 to 12 hours after oral dosing. Amlodipine's bioavailability is estimated to be between 64 - 90%. After 7-8 days of regular medication, steady-state plasma amlodipine levels are attained. Food does not affect absorption.

Telmisartan: Peak Telmisartan concentrations are reached at approximately 0.5–1 hours of oral ingestion. Consuming food decreases bioavailability, which causes a 6% drop in the plasma concentration-time curve for the 40 mg pill. The absolute bioavailability of telmisartan changes with dosage, 42% and 58% for 40 mg and 160 mg dosages, respectively. Its pharmacokinetics display nonlinearity in the 20–160 mg dosage range, with larger doses producing more than proportionate increases in plasma concentrations (Cmax and AUC). The half-life of Telmisartan is about 24 hours. With a repeated dosing accumulation index in plasma, a once-daily dose results in plasma concentrations at around 10–25% of peak values.

Distribution

Amlodipine: The plasma protein binding of Amlodipine is approximately 98%.

Telmisartan: High albumin levels and 1-acid glycoprotein binding levels are seen in plasma proteins. The estimated 500-litre volume of Telmisartan's dispersion suggests extra tissue binding.

Metabolism

Amlodipine: Amlodipine is primarily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10% of the parent compound and 60% of the metabolites.

Telmisartan: Telmisartan is metabolized via conjugation to produce an acyl glucuronide, the parent compound's glucuronide and the only metabolite detected in human plasma and urine. The metabolism of Telmisartan does not include the isoenzyme cytochrome P450. No matter the dose, Telmisartan's total plasma clearance is more significant than 800 mL/min.

Excretion

Amlodipine: Approximately 10% of a given dose is excreted in the urine.

Telmisartan: When 14C-labeled Telmisartan is delivered intravenously or orally, the bulk of the dosage is excreted in the faeces intact via biliary excretion, and only trace quantities were detected in the urine.

Therapeutic benefits of a combination of Amlodipine and telmisartan

• Blood pressure is lowered with the Amlodipine (calcium channel blocker) and Telmisartan (angiotensin II receptor blocker). This combination is highly beneficial for individuals whose hypertension is not sufficiently managed by a single medicine. Together, they effectively decrease blood pressure by focusing on several routes, lowering the risk of complications caused by hypertension.
• This combination can considerably lower the risk of cardiovascular events, including strokes and heart attacks, by lowering blood pressure. It reduces the workload on the cardiovascular system while protecting the heart and blood vessels.
• People who have renal disease, especially when it is accompanied by hypertension, benefit from a combination of Amlodipine and Telmisartan. By providing renal protection, it may delay the development of kidney disease.

• Moen, Marit D. "Telmisartan/amlodipine: single-pill combination in hypertension." American journal of Cardiovascular Drugs: drugs, devices, and other interventions vol. 10,6 (2010): 401-12. doi:10.2165/11204880-000000000-00000
• Sung, Ki-Chul et al. "Efficacy and safety of the low-dose antihypertensive combination of amlodipine, telmisartan, and chlorthalidone: A randomized, double-blind, parallel, phase II trial." Journal of clinical hypertension (Greenwich, Conn.) vol. 24,10 (2022): 1298-1309. doi:10.1111/jch.14570
• Kim, Tae-Seok et al. "Efficacy and Tolerability of Telmisartan/Amlodipine and Rosuvastatin Co-administration in Hypertensive Patients with Hyperlipidemia: A Phase III, Multicenter, Randomized, Double-blind Study." Clinical therapeutics vol. 41,4 (2019): 728-741. doi:10.1016/j.clinthera.2019.02.013
• Kim, BJ., Cho, KI., Kwon, H.M. et al. Effect of a fixed-dose combination of Telmisartan/S-amlodipine on circadian blood pressure compared with Telmisartan monotherapy: TENUVA-BP study. Clin Hypertens 28, 7 (2022). https://doi.org/10.1186/s40885-021-00184-0

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