CONSENSI® (amlodipine and celecoxib) tablets

CONSENSI® (amlodipine and celecoxib) tablets

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CONSENSI® (amlodipine and celecoxib) tablets

CONSENSI (amlodipine and celecoxib) tablet is an NSAID and long-acting calcium channel blocker for oral administration. Each tablet contains amlodipine besylate and celecoxib 3.47 mg/200 mg, 6.93 mg/200 mg, and 13.87 mg/200 mg and is equivalent to 2.5 mg/200 mg, 5 mg/200 mg, and 10 mg/200 mg amlodipine/celecoxib respectively.

Celecoxib is chemically designated as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The empirical formula is C17H14F3N3O2S, and the molecular weight is 381.38

Amlodipine besylate is chemically designated as 3-Ethyl-5-methyl (±)-2-[(2- aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate.The molecular formula is C20H25CIN2O5•C6H6O3S,and the molecular weight is 567.1

Indications and usage

CONSENSI is indicated in adult patients for whom treatment with both amlodipine for hypertension and celecoxib for osteoarthritis are appropriate.

Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal CVevents, 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: CONSENSI is only available in a celecoxib strength of 200 mg and is only to be taken once daily.

Mechanism of Action

The mechanism of action of CONSENSI is similar to the mechanism of action for its individual components, celecoxib and amlodipine, as described below.

Celecoxib: Celecoxib has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of COX-2. Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro.

Celecoxib concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Since celecoxib is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Amlodipine: Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites.

The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.

Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses.

Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Dosage and administration

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 with CONSENSI.

Start CONSENSI in adults at (amlodipine/celecoxib) 5 mg/200 mg orally once daily or 2.5 mg/200 mg in small, fragile, or elderly patients, or patients with mild hepatic insufficiency. Use 2.5 mg/200 mg when adding CONSENSI to other antihypertensive therapy. Adjust amlodipine component dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. If more rapid titration is clinically warranted, monitor closely. The maximum dose is 10 mg/200 mg once daily.

Discontinuation: If analgesic therapy is no longer indicated, discontinue CONSENSI and initiate patient on alternative antihypertensive therapy, such as amlodipine monotherapy. If CONSENSI is stopped and replaced with an equal dose of amlodipine, monitor blood pressure carefully.

Contraindications

CONSENSI is contraindicated in the following patients:

  • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to amlodipine, celecoxib, or any of the inactive ingredients in CONSENSI.
  • 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.
  • In the setting of coronary artery bypass graft (CABG) surgery.
  • In patients who have demonstrated allergic-type reactions to sulfonamides

Warnings and precautions

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in the treatment and may increase with duration of use.

CONSENSI is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

NSAIDs cause an increased risk of serious gastrointestinal (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.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue CONSENSI immediately, and perform a clinical evaluation of the patient.

NSAIDs, including celecoxib can lead to the new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics or loop diuretics may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure during the initiation of NSAID treatment and throughout the course of therapy.

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely. Monitor blood pressure carefully when switching between amlodipine and CONSENSI, and adjust dose accordingly.

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately doubling in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of myocardial infarction, hospitalization for heart failure, and death.

Long-term administration of NSAIDs 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. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors or the ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Celecoxib has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin sensitive asthma. Celecoxib is a sulfonamide and both NSAIDs and sulfonamides may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Seek emergency help if any anaphylactic reaction occurs.

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. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, celecoxib is contraindicated in patients with this form of aspirin sensitivity. When celecoxib is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as CONSENSI. 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. It is important to note that 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 CONSENSI and evaluate the patient immediately.

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Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with celecoxib has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

Adverse reactions

Cardiovascular: Vasculitis, deep venous thrombosis

General: Anaphylactoid reaction, angioedema

Liver and biliary: Liver necrosis, hepatitis, jaundice, hepatic failure

Hemic and lymphatic: Agranulocytosis, aplastic anemia, pancytopenia, leucopenia

Metabolic: Hypoglycemia, hyponatremia

Nervous: Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage

Renal: Interstitial nephritis

Drug interactions

Drugs That Interfere with Hemostasis:

Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.

Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.

Aspirin: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone.

ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers:

  • During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
  • During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function.
  • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis

Digoxin: The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.

Lithium: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.

Methotrexate: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity

Cyclosporine: Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function

Pemetrexed: Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).

CYP2C9 Inhibitors or Inducers: Celecoxib metabolism is predominantly mediated via CYP2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.

Corticosteroids: Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.

Use in specific populations

Pregnancy: Use of NSAIDs, including CONSENSI, 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 CONSENSI use between about 20 and 30 weeks of gestation and avoid CONSENSI use at about 30 weeks of gestation and later in pregnancy

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Lactation: The available published literature report the individual components of CONSENSI (celecoxib, amlodipine) are present in human breast milk at low levels. There is no available information on the effects of celecoxib or amlodipine on milk production.

Infertility: Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. 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, including celecoxib, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use: Safety and effectiveness of CONSENSI in pediatric patients have not been established.

Hepatic Impairment: The daily recommended dose of celecoxib in patients with moderate hepatic impairment (ChildPugh Class B) should be reduced by 50%. Because CONSENSI is not available in lower strengths of celecoxib, CONSENSI is not recommended in patients with moderate hepatic impairment. Additionally, the use of CONSENSI in patients with severe hepatic impairment is not recommended.

Renal Insufficiency: CONSENSI is not recommended in patients with severe renal insufficiency

Poor Metabolizers of CYP2C9 Substrates: In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C9*3/*3), based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) administer celecoxib starting with half the lowest recommended dose. Because CONSENSI is not available in lower strengths of celecoxib, CONSENSI is not recommended in patients who are known or suspected to be poor CYP2C9 metabolizers

Overdosage

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. GI bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare.

Manage patients by symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Amlodipine

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.

If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

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