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Product Name
:
MICARDROXI-EXTRA
Chemical Name
:
Telmisartan - Amlodipine
Therapeutic Category
:
Cardiovascular drugs
Pharmacologic Category
:
Angiotensin II Receptor Blocker/ Calcium Channel Blocker
Pharmaceutical Form
:
Tablets
Composition
:
Telmisartan 40mg + Amlodipine 5mg/ Telmisartan 80mg + Amlodipine 5mg/ Telmisartan 40mg + Amlodipine 10mg/ Telmisartan 80mg + Amlodipine 10mg
Dosing
 

Hypertension: Oral:

Initial therapy (antihypertensive naive): Telmisartan 40 mg/amlodipine 5 mg once daily; dose may be increased after 2 weeks of therapy. Patients requiring larger blood pressure reductions may be started on telmisartan 80 mg/amlodipine 5 mg once daily. Maximum recommended dose: Telmisartan 80 mg/day, amlodipine 10 mg/day

Add-on/replacement therapy: Telmisartan 40-80 mg and amlodipine 5-10 mg once daily depending upon previous doses, current control, and goals of therapy; dose may be titrated after 2 weeks of therapy. Maximum recommended dose: Telmisartan 80 mg/day; amlodipine 10 mg/day

Dosing: Geriatric

Not recommended for initial therapy in patients ≥75 years of age. For add-on/replacement therapy, initiate amlodipine therapy at 2.5 mg once daily and titrate slowly. Note: Use of individual agents may be necessary if the appropriate combination dose is not available. Note: Use as initial therapy is not an approved indication in the Canadian labeling.

Dosing: Renal Impairment

Mild-to-moderate impairment: No dosage adjustments are recommended.

Severe impairment: No dosage adjustments are recommended; titrate slowly.

Dosing: Hepatic Impairment Not recommended for initial therapy. For add-on/replacement therapy, initiate amlodipine at 2.5 mg once daily with low-dose telmisartan and titrate slowly
Use
 
Treatment of hypertension, including initial treatment in patients who will require multiple antihypertensives for adequate control
Adverse Reactions
 

>10%: Cardiovascular: Peripheral edema (dose related: 1% to 11%)

1% to 10%:

Cardiovascular: Orthostatic hypotension (6%), edema (<2%), hypotension (<2%), syncope (<2%)

Central nervous system: Dizziness (3%)

Neuromuscular & skeletal: Back pain (2%)

Contraindications
 

Hypersensitivity to amlodipine, telmisartan, or any component of the formulation; concomitant use with aliskiren in patients with diabetes mellitus

Warnings / Precautions Drug
 

Concerns related to adverse effects:

• Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of dihydropyridine calcium channel blockers. Reflex tachycardia may occur resulting in angina and/or MI in patients with obstructive coronary disease, especially in the absence of concurrent beta-blockade.

• Hyperkalemia: May occur with telmisartan use; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.

• Hypotension: Symptomatic hypotension may occur upon initiation in patients who are salt- or volume-depleted (eg, those treated with high-dose diuretics); correct volume depletion prior to administration. This transient hypotensive response is not a contraindication to further treatment with telmisartan/amlodipine.

• Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; use caution during initiation of therapy, particularly in patients with heart failure, volume or salt depletion, severe aortic stenosis, or in post-MI patients or those undergoing surgery or dialysis.

• Peripheral edema: The most common side effect of amlodipine is peripheral edema; occurs within 2-3 weeks of starting therapy.

• Renal function deterioration: Telmisartan may be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.

Disease-related concerns:

• Aortic stenosis: Use amlodipine with extreme caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.

• Heart failure (HF): Use caution when initiating in HF; may need to adjust dose, and/or concurrent diuretic therapy.

• Hepatic impairment: Use with caution in patients who have biliary obstructive disorders or hepatic impairment; amlodipine and telmisartan clearance is decreased so initiation at the lowest dose is recommended; the appropriate dose for hepatic impairment is not available in combination dosage form, therefore, initiation of treatment with this product is not recommended in patients with hepatic impairment. Canadian labeling contraindicates use in severe hepatic impairment or with biliary obstructive disorders.

• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use amlodipine with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition.

• Renal artery stenosis: Use telmisartan with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.

• Renal impairment: Use with caution in pre-existing renal insufficiency and severe renal impairment.

Concurrent drug therapy issues:

• Angiotensin-converting enzyme (ACE) inhibitors and renin inhibitors: Concomitant use of an ACE-inhibitor or renin inhibitor (eg, aliskiren) is associated with an increased risk of hypotension, hyperkalemia, and renal dysfunction; concurrent use with ramipril is not recommended. Concomitant use with aliskiren should be avoided in patients with GFR <60 mL/minute and is contraindicated in patients with diabetes mellitus (regardless of GFR).

Special populations:

• Elderly: Not recommended for initial therapy in patients ≥75 years of age. The appropriate combination dose is not available.

• Pregnancy: [U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

Interactions
 

ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy

Aliskiren: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the nephrotoxic effect of Angiotensin II Receptor Blockers. Management: Avoid aliskiren use with ACEIs or ARBs in patients with diabetes or estimated glomerular filtration rate below 60 mL/min. In other patients receiving these combinations, monitor serum potassium, serum creatinine, and blood pressure periodically. Risk D: Consider therapy modification

Alpha1-Blockers: May enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Antifungal Agents (Azole Derivatives, Systemic): May enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Management: Concurrent use of felodipine or nisoldipine with itraconazole is specifically contraindicated. Frequent monitoring is warranted with any such combination; calcium channel blocker dose reductions may be required. Risk D: Consider therapy modification

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

Atosiban: Calcium Channel Blockers may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Calcium Channel Blockers. Management: Monitor for decreased therapeutic effects of calcium channel blockers with concomitant barbiturate therapy. Calcium channel blocker dose adjustments may be necessary. Nimodipine Canadian labeling contraindicates concomitant use with phenobarbital. Risk C: Monitor therapy

Beta-Blockers: Calcium Channel Blockers (Dihydropyridine) may enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): Calcium Channel Blockers (Dihydropyridine) may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy

Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Risk C: Monitor therapy

Canagliflozin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Canagliflozin may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Calcium Channel Blockers (Dihydropyridine). Management: Consider calcium channel blocker (CCB) dose adjustments or alternative therapy in patients receiving concomitant carbamazepine. Nimodipine Canadian labeling contraindicates concurrent use with carbamazepine. Risk D: Consider therapy modification

Cardiac Glycosides: Telmisartan may increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Clopidogrel: Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination

CycloSPORINE (Systemic): May decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy

CycloSPORINE (Systemic): Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of CycloSPORINE (Systemic). Risk C: Monitor therapy

CYP1A2 Substrates: CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Fluconazole: May decrease the metabolism of Calcium Channel Blockers. Risk C: Monitor therapy

Fosphenytoin: Calcium Channel Blockers may increase the serum concentration of Fosphenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Risk D: Consider therapy modification

Grapefruit Juice: May increase the serum concentration of AmLODIPine. Risk C: Monitor therapy

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Management: Consider avoiding CYP3A4 inducing herbs in order to avoid therapeutic failure of the substrate. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Risk D: Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Limit the maximum adult dose of lomitapide to 30 mg daily when used in combination with any weak CYP3A4 inhibitor. Risk D: Consider therapy modification

Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Management: Consider using a noninteracting macrolide. Monitor for increased therapeutic effects of calcium channel blockers if an interacting macrolide antibiotic is initiated, or decreased effects if a macrolide is discontinued. Exceptions: Azithromycin (Systemic); Fidaxomicin; Spiramycin. Risk D: Consider therapy modification

Magnesium Salts: Calcium Channel Blockers may enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy

Melatonin: May diminish the antihypertensive effect of Calcium Channel Blockers (Dihydropyridine). Risk C: Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Risk D: Consider therapy modification

Nafcillin: May increase the metabolism of Calcium Channel Blockers. Risk D: Consider therapy modification

Neuromuscular-Blocking Agents (Nondepolarizing): Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy

Nitroprusside: Calcium Channel Blockers may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Phenytoin: Calcium Channel Blockers may increase the serum concentration of Phenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Risk D: Consider therapy modification

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination

Pirfenidone: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: This combination may be used with caution only if the moderate CYP1A2 inhibitor does not significantly inhibit other CYP enzymes and the patient is not taking any other drugs that do significantly inhibit other specific CYP enzymes. Risk X: Avoid combination

Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Protease Inhibitors: May decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Risk D: Consider therapy modification

QuiNIDine: May increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Calcium Channel Blockers (Dihydropyridine) may decrease the serum concentration of QuiNIDine. Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of QuiNIDine. Risk C: Monitor therapy

Ramipril: Telmisartan may increase the serum concentration of Ramipril. Concentrations of the active metabolite, ramiprilat, may also be increased. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Management: The labeling for some U.S. and Canadian calcium channel blockers contraindicate use with rifampin however recommendations vary. Consult appropriate labeling. Risk D: Consider therapy modification

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification

Simvastatin: AmLODIPine may increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of amlodipine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day (for adults). Risk D: Consider therapy modification

Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ARBs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification

Tacrolimus (Systemic): Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Pregnancy
 
Pregnancy Risk Factor

D ( show table )

Pregnancy Implications

[U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. Also see individual agents.

Lactation
 

Excretion in breast milk unknown/not recommended

Breast-Feeding Considerations

See individual agents.

Monitoring Parameters
 
Baseline and periodic electrolyte panels (especially serum potassium); renal function (serum creatinine, BUN, urinalysis); hepatic function; heart rate, blood pressure, symptomatic hypotension, peripheral edema
Mechanism of Action
 

Telmisartan is a nonpeptide AT1 (angiotensin II type 1) receptor antagonist. Angiotensin II acts as a vasoconstrictor. In addition to causing direct vasoconstriction, angiotensin II also stimulates the release of aldosterone. Once aldosterone is released, sodium and water are reabsorbed. The end result is an elevation in blood pressure. Telmisartan binding to AT1 prevents angiotensin II from binding to the receptor thereby blocking the vasoconstriction and the aldosterone secreting effects of angiotensin II.

Amlodipine inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina. Amlodipine directly acts on vascular smooth muscle to produce peripheral arterial vasodilation reducing peripheral vascular resistance and blood pressure.

Pharmacodynamics / Kinetics
 
Telmisartan

Orally active, not a prodrug

Onset of action: 1-2 hours

Duration: Up to 24 hours

Distribution: V d : 500 L

Protein binding: >99.5%; primarily to albumin and alpha 1 -acid glycoprotein

Metabolism: Hepatic via conjugation to inactive metabolites; not metabolized via CYP

Bioavailability (dose dependent): 42% to 58%; Hepatic impairment: Approaches 100%

Half-life elimination: Terminal: 24 hours

Time to peak, plasma: 0.5-1 hours

Excretion: Feces (97%)

Clearance: Total body: 800 mL/minute


Amlodipine

Duration of antihypertensive effect: 24 hours

Absorption: Oral: Well absorbed

Distribution: V d : 21 L/kg

Protein binding: 93% to 98%

Metabolism: Hepatic (>90%) to inactive metabolites

Bioavailability: 64% to 90%

Half-life elimination: Terminal: 30-50 hours; increased with hepatic dysfunction

Time to peak, plasma: 6-12 hours

Excretion: Urine (10% of total dose as unchanged drug, 60% of total dose as metabolites)

 
   
 
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