amlodipine/celecoxib (Rx)

>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%)

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 reaction with eosinophilia and systemic symptoms (DRESS)

• Drug Reaction reported in patients taking NSAIDs; some of these events have been fatal or life-threatening; DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling
• Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis; sometimes symptoms of DRESS may resemble an acute viral infection
• Eosinophilia is often present; because this disorder is variable in its presentation, other organ systems not noted here may be involved
• Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident; if such signs or symptoms are present, discontinue therapy and evaluate the patient immediately

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

Pregnancy

There are no adequate and well-controlled studies in pregnant women; data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive

Clinical considerations

• In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth

Fetal toxicity

• Use of NSAIDs can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment
• Because of these risks, limit dose and duration of use between about 20 and 30 weeks of gestation and avoid use at about 30 weeks of gestation and later in pregnancy
• Use of NSAIDs at about 30 weeks gestation or later in pregnancy increases risk of premature closure of fetal ductus arteriosus
• Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment
• There are no available data with use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage; however, there are published studies with each individual component of the drug combination
• Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive
• In animal reproduction studies, there were no clear developmental effects at doses up to 0.4-times the maximum recommended human dose (MRHD) in the rabbit and 0.5-times in the MRHD rat when dosed throughout gestation
• In contrast, an increase in membranous ventricular septal defects was reported in rats treated on gestation days 9 & 10 with 0.8-times the MRHD
• Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre-and post-implantation loss
• Prostaglandins also have been shown to have an important role in fetal kidney development; in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses
• Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, can cause premature closure of fetal ductus arteriosus
• If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit use to lowest effective dose and shortest duration possible
• If treatment is needed for a pregnant woman, consider monitoring with ultrasound for oligohydramnios; if oligohydramnios occurs, discontinue therapy and follow up according to clinical practice

Labor or delivery

• There are no studies on the effects of celecoxib during labor or delivery
• In animal studies, NSAIDs inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth

Infertility

• Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation
• Consider withdrawal of NSAIDs in women who have difficulties conceiving or who are undergoing investigation of infertility

Animal studies

• Administration during pregnancy resulted in adverse effects on development, including increases in embryonic death and fetal malformations, at doses or maternal plasma drug exposures greater than those used clinically
• Prostaglandins have shown an important role in endometrial vascular permeability, blastocyst implantation, and decidualization; in animal studies, administration of prostaglandin synthesis inhibitors resulted in increased pre-and postimplantation loss

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

Lactation

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

Celecoxib

• Limited data from 12 breastfeeding women showed low levels of celecoxib in breast milk
• Calculated average daily infant dose was 10-40 mcg/kg/day, <1% of the weight-based therapeutic dose for a 2-year old child
• There is no information available regarding effects of drug on milk production; the developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from drug or from underlying maternal condition

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)

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.

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

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