Included as part of the "PRECAUTIONS" Section
Cardiovascular Thrombotic Events
Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
In the APC (Adenoma Prevention with Celecoxib) trial, there was about a threefold increased risk of the composite endpoint of cardiovascular death, myocardial infarction, or stroke for the celecoxib 400 mg twice daily and celecoxib 200 mg twice daily treatment arms compared to placebo. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [see Clinical Studies].
A randomized controlled trial entitled the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION) was conducted to assess the relative cardiovascular thrombotic risk of a COX-2 inhibitor, celecoxib, compared to the non-selective NSAIDs naproxen and ibuprofen. Celecoxib 100 mg twice daily was non-inferior to naproxen 375 to 500 mg twice daily and ibuprofen 600 to 800 mg three times daily for the composite endpoint of the Antiplatelet Trialists’ Collaboration (APTC), which consists of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, and non-fatal stroke [see Clinical Studies].
To minimize the potential risk for an adverse CV event in celecoxib-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as celecoxib, increases the risk of serious GI events [see Gastrointestinal Bleeding, Ulceration, And Perforation].
Status Post CABG Surgery
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 myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS].
Post-Myocardial Infarction Patients
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-myocardial infarction period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-myocardial infarction was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-myocardial infarction, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of celecoxib in patients with a recent myocardial infarction unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If celecoxib is used in patients with a recent myocardial infarction, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And Perforation
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. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with celecoxib. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
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 to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose aspirin (ASA). Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [see Clinical Studies].
Strategies to Minimize the GI Risks in NSAID-Treated Patients:
- Use the lowest effective dosage for the shortest possible duration.
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
- Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
- If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue CONSENSI until a serious GI adverse event is ruled out.
- In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see DRUG INTERACTIONS].
Hepatotoxicity And Patients With Hepatic Failure
Elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including celecoxib.
In controlled clinical trials of celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the ULN) of liver associated enzymes was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST.
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.
Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with impaired hepatic function.
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 [see DRUG INTERACTIONS].
see Clinical Studies for additional blood pressure data for celecoxib.
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.
Increased Angina Or Myocardial Infarction
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.
Heart Failure And Edema
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.
Additionally, fluid retention and edema have been observed in some patients taking NSAIDs. Use of celecoxib may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see DRUG INTERACTIONS].
In the CLASS study [see Clinical Studies], the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on celecoxib 400 mg twice daily (4-fold and 2-fold the recommended osteoarthritis and rheumatoid arthritis dose, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively.
Avoid the use of celecoxib in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If celecoxib is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia
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.
No information is available from controlled clinical studies regarding the use of celecoxib in patients with advanced renal disease. The renal effects of celecoxib may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating celecoxib. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of celecoxib [see DRUG INTERACTIONS]. Avoid the use of celecoxib in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If celecoxib is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism 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 [see CONTRAINDICATIONS and Exacerbation Of Asthma Related To Aspirin Sensitivity].
Seek emergency help if any anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin Sensitivity
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 [see CONTRAINDICATIONS]. When celecoxib is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
Serious skin reactions have occurred following treatment with celecoxib, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). These serious events may occur without warning and can be fatal.
Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of celecoxib at the first appearance of skin rash or any other sign of hypersensitivity.
Celecoxib is contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS].
Premature Closure Of Fetal Ductus Arteriosus
Celecoxib may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including celecoxib, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use In Specific Populations].
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.
In controlled clinical trials the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.
NSAIDs, including celecoxib, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see DRUG INTERACTIONS].
Masking Of Inflammation And Fever
The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Gastrointestinal Bleeding, Ulceration, And Perforation, Hepatotoxicity And Patients With Hepatic Failure, Renal Toxicity And Hyperkalemia].
In controlled clinical trials, elevated blood urea nitrogen (BUN) occurred more frequently in patients receiving celecoxib compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with CONSENSI and periodically during therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see WARNINGS AND PRECAUTIONS].
Gastrointestinal Bleeding, Ulceration, And Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see WARNINGS AND PRECAUTIONS].
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop CONSENSI and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Instruct patients to return to their healthcare provider if symptoms of hypotension (e.g., lethargy, light headedness, or syncope) develop [see WARNINGS AND PRECAUTIONS].
Increased Angina Or Myocardial Infarction
Warn patients that worsening of their angina or myocardial infarction can develop after starting CONSENSI or switching to a higher strength amlodipine formulation of CONSENSI, particularly in patients with severe obstructive coronary artery disease [see WARNINGS AND PRECAUTIONS].
Heart Failure And Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see WARNINGS AND PRECAUTIONS].
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Serious Skin Reactions
Advise patients to stop CONSENSI immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS].
Advise females of reproductive potential who desire pregnancy that NSAIDs, including CONSENSI, may be associated with a reversible delay in ovulation [see Use In Specific Populations].
Advise pregnant women to avoid use of CONSENSI and other NSAIDs starting at 30 weeks of gestation because of the risk of the premature closing of the fetal ductus arteriosus. Advise females of reproductive potential to contact their healthcare provider with a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Avoid Concomitant Use Of NSAIDs
Inform patients that the concomitant use of CONSENSI with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of GI toxicity, and little or no increase in efficacy [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use Of NSAIDS And Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with CONSENSI until they talk to their healthcare provider [see DRUG INTERACTIONS].
Discontinuation Of CONSENSI
Inform patients not to discontinue CONSENSI without discussing with their healthcare provider because an alternative blood pressure lowering drug should be started to control blood pressure [see DOSAGE AND ADMINISTRATION].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Combination Of Celecoxib And Amlodipine
No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of celecoxib and amlodipine. However, these studies have been conducted for celecoxib and amlodipine alone.
Celecoxib was not carcinogenic in Sprague-Dawley rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females (approximately 2-to 4-times the human exposure as measured by the AUC0-24 at 200 mg twice daily) or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females (approximately equal to human exposure as measured by the AUC0-24 at 200 mg twice daily) for two years.
Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow.
Impairment of Fertility
Celecoxib had no effect on male or female fertility or male reproductive function in rats at oral doses up to 600 mg/kg/day (approximately 11-times human exposure at 200 mg twice daily based on the AUC0-24). At ≥50 mg/kg/day (approximately 6-times human exposure based on the AUC0-24 at 200 mg twice daily) there was increased preimplantation loss.
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose of 10 mg amlodipine/day (based on patient weight of 50 kg). For the rat, the highest dose was, on a mg/m2 basis, about twice the maximum recommended human dose (based on patient weight of 50 kg).
Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day [8 times the maximum recommended human dose (based on patient weight of 50 kg) of 10 mg/day on a mg/m2 basis].
Use In Specific Populations
Use of NSAIDs, including CONSENSI, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including CONSENSI, in pregnant women starting at 30 weeks of gestation (third trimester) (see Clinical Considerations, Data). There is no published literature of CONSENSI in pregnant women. No animal reproductive toxicity studies have been conducted with the combination of celecoxib and amlodipine.
The available published data and case reports did not identify a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Published literature reports that use of NSAIDs, including celecoxib, during the third trimesters of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimester of pregnancy are inconclusive. (see Clinical Considerations, Data). In animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 6 times the maximum recommended human dose of 200 mg twice daily. In addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 2 times the maximum recommended human dose (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 celecoxib, resulted in increased pre-and post-implantation loss, and decreased uterine decidualization (see Data).
The available data from post-marketing reports and a small study with Norvasc 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 (see Clinical Considerations, Data). In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20-times the MRHD, respectively. However, in rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Disease-Associated Maternal and/or Embryo/Fetal Risk
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.
Fetal/Neonatal Adverse Reactions
Avoid use of NSAID’s in pregnant women in the third trimester because NSAIDs, including celecoxib, can cause premature closure of the fetal ductus arteriosus (see Data).
Labor or Delivery
There are no studies on the effects of CONSENSI during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth (see Data).
Published literature has concluded that the use of NSAIDs during the third trimester of pregnancy may cause constriction of the patent ductus arteriosus and premature closure of the fetal ductus arteriosus.
Celecoxib at oral doses ≥150 mg/kg/day (approximately 2 times the human exposure at 200 mg twice daily as measured by AUC0-24), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6 times human exposure based on the AUC0-24 at 200 mg twice daily for rheumatoid arthritis) throughout organogenesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses at oral doses ≥50 mg/kg/day (approximately 6 times human exposure based on the AUC0-24 at 200 mg twice daily for rheumatoid arthritis). Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the AUC0-24 at 200 mg twice daily).
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However, for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
The available published literature report the individual components of CONSENSI (celecoxib, amlodipine) are present in human breast milk at low levels. Data from 3 published reports that included a total of 12 breastfeeding women calculated the average daily infant dose of celecoxib as 10-40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events with maternal use of celecoxib. Data from a published observational clinical lactation study reports that amlodipine is present at an estimated median relative infant dose of 4.2%, approximately 1.7 to 3.3% of the recommended dose for an average 6-year old (20 kg) (see Data). No adverse effects of amlodipine were observed in the breastfed infants. There is no available information on the effects of celecoxib or amlodipine on milk production.
A clinical lactation study in six volunteers administered a single oral dose of 200 mg celecoxib [median maternal celecoxib dose of 3.3 mg/kg (range of 2.3-3.7)] at 6.5 to 15 months postpartum (mean 11 months) and in the final stage of weaning. showed that the median total amount of celecoxib present in milk was 0.011 mg (range 0.004-0.042) or 0.04% (range 0.010.15) of the maternal single dose (weight adjusted). The estimated daily infant dose was 0.013 mg/kg/day (range 0.0110.021), which is 0.13 to 0.33% of the clinically used celecoxib dose for pediatric patients.
A clinical lactation study in three breastfeeding mothers who had been taking 200 mg celecoxib orally once daily for many weeks and who were at steady state (group 1) and two breastfeeding mothers administered a single 200-mg oral dose of celecoxib (group 2) averaging 12 months post-partum (range 3-22 months). The mean average concentration of celecoxib in milk during the 8-hour interval following administration of celecoxib for all five mothers was 66 μg/L (95% CI: 41-89). The estimated mean absolute infant dose was 9.8 μg/kg/day (95% CI: 6.2-13.4), which is 0.1 to 0.25% of the dose clinically used for pediatric patients. Comparison of this to the weight-normalized maternal dose yields an estimated mean relative infant dose of 0.30% (95% CI: 0.19-0.39)
An observational clinical lactation study of 31 lactating women who were receiving amlodipine within 3 weeks after delivery for pregnancy-induced hypertension showed a median concentration of amlodipine in milk 24 hours after a mean maternal oral dose of approximately 6 mg/day for 7 to 9 days of 11.5 ng/mL (interquartile range of 9.84-18.0 ng/mL). The mean maternal body weight-adjusted dose was 0.0987 ± 0.0366 mg/kg. The median plasma concentration of amlodipine was 15.5 (interquartile range of 12.0-22.8 ng/mL). The median amlodipine concentration ratio of milk to plasma was 0.85 (interquartile range of 0.743-1.08). The median estimated infant daily dose was 4.17 μg/kg/day (interquartile range of 3.05 to 6.32 μg/kg/day), approximately 1.7 to 3.3% of the recommended dose for an average 6-year old (20 kg). The median relative infant daily dose was 4.18% (interquartile range of 3.12%-7.25%).
Females And Males Of Reproductive Potential
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.
Safety and effectiveness of CONSENSI in pediatric patients have not been established.
Combination Of Celecoxib And Amlodipine
In the short-term controlled clinical trial of the combination of celecoxib and amlodipine in patients with newly diagnosed hypertension whom required pharmacological therapy to control their hypertension (Study No. KIT-302-03-01), 24.5% of patients treated with the combination were ≥65 years of age. No examinations of age subgroups were planned by protocol or performed, because of the limited sample size.
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious CV, GI, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see WARNINGS AND PRECAUTIONS]. Because CONSENSI is not available in lower strengths of celecoxib, CONSENSI is not recommended in patients that require dosages other than 200 mg of celecoxib once daily.
Of the total number of patients who received celecoxib in pre-approval clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the glomerular filtration rate (GFR), BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients [see WARNINGS AND PRECAUTIONS].
Clinical studies of amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, 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 clearance of amlodipine with a resulting increase of AUC of approximately 40–60%, and a lower initial dose may be required [see DOSAGE AND ADMINISTRATION].
The daily recommended dose of celecoxib in patients with moderate hepatic impairment (Child-Pugh 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 [see CLINICAL PHARMACOLOGY].
CONSENSI is not recommended in patients with severe renal insufficiency [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
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 [see CLINICAL PHARMACOLOGY].