amlodipine/celecoxib (Rx)

Brand and Other Names:Consensi
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

amlodipine/celecoxib

tablet

  • 2.5mg/200mg
  • 5mg/200mg
  • 10mg/200mg

Osteoarthritis & Hypertension

Indicated in adults for whom treatment with both amlodipine for hypertension and celecoxib for osteoarthritis are appropriate (also see Dosing Considerations)

Use the lowest effective dosage of celecoxib for the shortest duration consistent with individual patient treatment goals

Only 200 mg of celecoxib once daily is available for each dosage strength

Initial: 5 mg/200 mg PO qDay or 2.5 mg/200 mg in small, fragile, or elderly patients, or patients with mild hepatic insufficiency

Use 2.5 mg/200 mg amlodipine/celecoxib when adding to other antihypertensive therapy

Adjust amlodipine component dosage according to blood pressure goals; in general, wait 7-14 days between titration steps; if more rapid titration is clinically warranted, monitor closely

Not to exceed 10 mg/200 mg qDay

Dosage Modifications

Hepatic impairment

  • Mild (Child-Pugh A): Initiate at lower dose of 2.5 mg/200mg
  • Moderate (Child-Pugh B): Not recommended; daily recommended dose of celecoxib in patients with moderate hepatic impairment should be reduced by 50%, however, because the combination only has a single dosage strength of celecoxib 200 mg, it is not recommended
  • Severe (Child-Pugh C): Not recommended

Renal impairment

  • Mild or moderate: No dose adjustment required
  • Severe (CrCl <30 mL/min): Not recommended (NSAIDs are not recommended with severe renal insufficiency)

Dosing Considerations

Additional information regarding indications

  • Amlodipine is indicated for hypertension, to lower blood pressure; lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarctions
  • Amlodipine may be used alone or in combination with other antihypertensive agents
  • Celecoxib is indicated for the management of the signs and symptoms of osteoarthritis

Limitations of use

  • Inappropriate for short-term or intermittent treatment or to treat any conditions other than hypertension in patients taking celecoxib for osteoarthritis
  • Only available in a celecoxib strength of 200 mg and is only to be taken once daily

Safety and efficacy not established

Dosage Forms & Strengths

amlodipine/celecoxib tablets

2.5mg/200mg

5mg/200mg

10mg/200mg

Osteoarthritis & Hypertension

Indicated in adults for whom treatment with both amlodipine for hypertension and celecoxib for osteoarthritis are appropriate (also see Dosing Considerations)

Use the lowest effective dosage of celecoxib for the shortest duration consistent with individual patient treatment goals

Only 200 mg of celecoxib once daily is available for each dosage strength

Initial: 2.5 mg/200 mg PO qDay in small, fragile, or elderly patients, or patients with mild hepatic insufficiency

Dosing Considerations (additional information regarding indications)

Amlodipine is indicated for hypertension, to lower blood pressure; lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarctions

Amlodipine may be used alone or in combination with other antihypertensive agents

Celecoxib is indicated for the management of the signs and symptoms of osteoarthritis

Dosing Considerations (limitations of use)

Inappropriate for short-term or intermittent treatment or to treat any conditions other than hypertension in patients taking celecoxib for osteoarthritis

Only available in a celecoxib strength of 200 mg and is only to be taken once daily

Dosing Considerations (geriatric use)

Celecoxib: Elderly patients, compared with younger patients, are at greater risk for NSAID-associated serious CV, GI, and/or renal adverse reactions

Amlodipine: Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy; elderly patients have decreased amlodipine clearance with a resulting increased AUC of ~40-60%, and a lower initial dose is recommended

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Interactions

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            Adverse Effects

            >10%

            Celecoxib

            • Headache (15.8%)

            Amlodipine

            • Edema (1.8-14.6%)

            1-10% (amlodipine)

            Fatigue (4.5%)

            Flushing (0.7-4.5%)

            Dizziness (1.1-3.4%)

            Palpitations (0.7-3.3%)

            Nausea (2.9%)

            Abdominal pain (1.6%)

            Somnolence (1.3-1.6%)

            1-10% (celecoxib)

            Dyspepsia (8.8%)

            Upper respiratory tract infection (8.1%)

            Diarrhea (5.6%)

            Sinusitis (5%)

            Abdominal pain (4.1%)

            Nausea (3.5%)

            Back pain (2.8%)

            Insomnia (2.3%)

            Pharyngitis (2.3%)

            Rash (2.2%)

            Flatulence (2.2%)

            Peripheral edema (2.1%)

            Dizziness (2%)

            Rhinitis (2%)

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            Warnings

            Black Box Warnings

            Cardiovascular thrombotic events

            • NSAIDs cause an increased risk of serious CV thrombotic events, including MI and stroke, which can be fatal
            • This risk may occur early in the treatment and may increase with duration of use
            • NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery

            GI bleeding, ulceration, and perforation

            • NSAIDs cause an increased risk of serious GI adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal
            • These events can occur at any time during use and without warning symptoms
            • Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events

            Contraindications

            Known hypersensitivity (eg, anaphylactic reactions and serious skin reactions) to amlodipine, celecoxib, or any of the inactive ingredients

            History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs; severe, sometimes fatal, anaphylactic reactions to NSAIDs, have been reported in such patients

            Demonstrated allergic-type reactions to sulfonamides

            In the setting of CABG surgery

            Cautions

            Celecoxib may cause premature closure of the ductus arteriosus; avoid

            NSAIDs in pregnant women starting at 30 weeks of gestation

            Celecoxib may increase risk of bleeding events; anemia reported

            Because celecoxib reduces inflammation and possibly fever, diagnostic signs for detecting infection may be diminished

            Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider periodically monitoring patients on long-term NSAIDs with a complete CBC and a chemistry profile

            Cardiovascular events

            • Also see Black Box Warnings and Contraindications
            • Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs have shown an increased risk of serious CV thrombotic events, including MI and stroke, which can be fatal
            • Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of MI and stroke; NSAIDs are contraindicated in the setting of CABG
            • Observational studies conducted in the Danish National Registry found patients treated with NSAIDs post-MI were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment; avoid NSAIDs in patients following recent MI
            • Randomized controlled trials demonstrated an approximately doubling in hospitalizations for heart failure (HF) in COX-2 selective-treated patients and nonselective NSAID treated patients; avoid use with severe HF
            • NSAIDs may lead to new-onset hypertension or worsening of preexisting hypertension
            • Amlodipine may worsen angina, and acute MI can develop after starting or increasing the dose, particularly in patients with severe obstructive coronary artery disease
            • Amlodipine may cause symptomatic hypotension, particularly in patients with severe aortic stenosis

            GI bleeding, ulceration, and perforation

            • Also see Black Box Warnings
            • NSAIDs, including celecoxib, cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal
            • Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic
            • Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared with patients without these risk factors

            Hepatotoxicity and patients with hepatic impairment

            • Also see Dosage Modifications
            • Elevated ALT or AST (≥3 x ULN) reported in ~1% of NSAID-treated patients in clinical trials
            • Rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure, have also been reported with NSAIDs
            • Amlodipine is extensively metabolized by the liver, and the plasma elimination half-life is 56 hr in patients with impaired hepatic function

            Renal toxicity and hyperkalemia

            • Long-term NSAID use has resulted in renal papillary necrosis and other renal injury
            • Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion
            • Patients at greatest risk are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction; those taking diuretics, ACE-inhibitors, or ARBs; and elderly individuals
            • Increased serum potassium, including hyperkalemia, reported with NSAIDs, even without renal impairment; this is attributed to a hyporeninemic-hypoaldosteronism state

            Anaphylactic, asthma exacerbation, and serious skin reactions

            • Also see Contraindications
            • Celecoxib is a sulfonamide; has been associated with anaphylactic reactions, including in patients with aspirin-sensitive asthma
            • A subpopulation of patients with asthma may have aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs
            • Serious skin reactions have occurred following treatment with celecoxib, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis; these serious events may occur without warning and can be fatal

            Drug interaction overview

            • Celecoxib
              • Coadministration with anticoagulants or antiplatelets (eg, ASA, SSRIs) have a synergistic effect on bleeding
              • NSAIDs may decrease antihypertensive effects of ACE inhibitors, ARBs, or beta-blockers
              • NSAIDs may reduce natriuretic effect of loop diuretics and thiazide diuretics
              • Celecoxib may prolong digoxin elimination half-life
              • NSAIDs may elevate plasma lithium levels and reduce renal lithium clearance
              • Coadministration with methotrexate may increase risk of methotrexate toxicity (eg, neutropenia, thrombocytopenia, renal dysfunction)
              • Coadministration with cyclosporine may increase cyclosporine’s risk for nephrotoxicity
              • Coadministration with other NSAIDs or salicylates increases risk of GI toxicity, with little or no increase in analgesic efficacy
              • Coadministration with corticosteroids may increase risk of GI ulceration or bleeding
              • Coadministration with pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity
              • Celecoxib metabolism is primarily via CYP2C9 in the liver; coadministration with CYP2C9 inhibitors or inducers may increase toxicity or reduce efficacy, respectively
              • Celecoxib may inhibit CYP2D6; may increase systemic exposure of CYP2D6 substrates
            • Amlodipine
              • Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction
              • If coadministered with CYP3A inducers, monitor blood pressure to assure efficacy
              • Amlodipine may increase systemic exposure of simvastatin; limit simvastatin dose to 20 mg/day if coadministered
              • Amlodipine may increase systemic exposure of cyclosporine or tacrolimus; monitor trough cyclosporine or tacrolimus levels and adjust dose when appropriate
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            Pregnancy

            Pregnancy

            Celecoxib: Avoid use of NSAIDs in pregnant women starting at 30 weeks' gestation; use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus

            Amlodipine: Available data from postmarketing reports and a small study with amlodipine use in pregnant women with mild-to-moderate chronic hypertension did not identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy

            Infertility

            • Females: Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs may delay or prevent rupture of ovarian follicles

            Lactation

            Celecoxib: Estimated mean absolute infant dose 9.8 mcg/kg/day, which is 0.1-0.25% of the dose clinically used for pediatric patients

            Amlodipine: Estimated median infant dose 4.17 mcg/kg/day, which is ~1.7-3.3% of the recommended dose for an average 6-year-old (20 kg)

            The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child or from the underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Celecoxib: Inhibits cyclooxygenase (COX)-2; does not affect COX-1 (at therapeutic concentrations), thereby decreasing formation of prostaglandin synthesis; has analgesic, anti-inflammatory, and antipyretic properties

            Amlodipine: Inhibits transmembrane influx of extracellular calcium ions across membranes of myocardial cells and vascular smooth muscle cells without changing serum calcium concentrations; this inhibits cardiac and vascular smooth muscle contraction, thereby dilating main coronary and systemic arteries

            In clinical trials, the combination lowered diastolic and systolic blood pressure (both daytime and nighttime measurements) similarly to an equal dose of amlodipine

            Absorption

            Absolute bioavailability: 64-90% (amlodipine)

            Peak plasma time

            • Amlodipine: 6-12 hr
            • Celecoxib: 2-3 hr

            Distribution

            Vd: 400 L (celecoxib)

            Protein bound

            • Amlodipine: 93%
            • Celecoxib: 97%

            Metabolism

            Celecoxib: Primarily in liver by CYP2C9

            Amlodipine: Extensively (~90%) converted to inactive metabolites via hepatic metabolism

            Elimination

            Clearance: 500 mL/min (celecoxib)

            Half-life

            • Amlodipine: 30-50 hr
            • Celecoxib: 11 hr

            Excretion

            • Amlodipine: 10% (parent drug) and 60% metabolites in urine
            • Celecoxib: <3% unchanged drug in urine and feces

            Pharmacogenomics

            CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity (eg, individuals who are homozygous for the CYP2C9*2 and CYP2C9*3 polymorphisms)

            Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C9*3/*3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared with subjects with CYP2C9*1/*1 or *I/*3 genotypes

            Pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms (eg, *2, *5, *6, *9 and *11)

            Estimated frequency of the homozygous *3/*3 genotype is 0.3-1% in various ethnic groups

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            Administration

            Oral Administration

            May take with or without food

            Discontinuation

            • If analgesic therapy is no longer indicated, discontinue amlodipine/celecoxib and initiate patient on alternative antihypertensive therapy
            • If amlodipine/celecoxib is stopped and replaced with an equal dose of amlodipine, monitor blood pressure carefully

            Replacement therapy

            • For patients receiving celecoxib and amlodipine from separate capsules and tablets, respectively, substitute amlodipine/celecoxib containing the same component doses; not to exceed 10mg/200 mg qDay
            • Monitor blood pressure carefully

            Storage

            Store at room temperature 20-25°C (68-77°F)

            Dispense in tight, light-resistant containers

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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