WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS
WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS
See full prescribing information for complete boxed warning
Dolcelox may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (5.1,14.6)
Dolcelox is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1)
NSAIDs, including Dolcelox, cause an increased risk of serious gastrointestinal 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 are at greater risk for serious gastrointestinal (GI) events. (5.4)
Dolcelox may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All nonsteroidal anti-inflammatory drugs (NSAIDs) may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (5.1,14.6)
Dolcelox is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1)
NSAIDs, including Dolcelox, cause an increased risk of serious gastrointestinal 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 are at greater risk for serious gastrointestinal events. (5.4)
1. INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of Dolcelox and other treatment options before deciding to use Dolcelox. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ]
Dolcelox is a nonsteroidal anti-inflammatory drug indicated for:
Osteoarthritis (OA) (1.1)
Rheumatoid Arthritis (RA) (1.2)
Juvenile Rheumatoid Arthritis (JRA) in patients 2 years and older (1.3)
Ankylosing Spondylitis (AS) (1.4)
Acute Pain (AP) (1.5)
Primary Dysmenorrhea (PD) (1.6)
1.1 Osteoarthritis (OA)
Dolcelox is indicated for relief of the signs and symptoms of OA [see Clinical Studies (14.1) ]
1.2 Rheumatoid Arthritis
Dolcelox is indicated for relief of the signs and symptoms of RA [see Clinical Studies (14.2) ]
1.3 Juvenile Rheumatoid Arthritis
Dolcelox is indicated for relief of the signs and symptoms of JRA in patients 2 years and older [see Clinical Studies (14.3) ]
1.4 Ankylosing Spondylitis
Dolcelox is indicated for the relief of signs and symptoms of AS [see Clinical Studies (14.4) ]
1.5 Acute Pain
Dolcelox is indicated for the management of AP in adults [see Clinical Studies (14.5) ]
1.6 Primary Dysmenorrhea
Dolcelox is indicated for the treatment of PD [see Clinical Studies (14.5) ]
2. DOSAGE AND ADMINISTRATION
Use lowest effective dose for the shortest duration consistent with treatment goals for the individual patient.
These doses can be given without regard to timing of meals.
Use lowest effective dose for the shortest duration consistent with treatment goals for the individual patient.
OA: 200 mg once daily or 100 mg twice daily (2.1, 14.1)
RA: 100 to 200 mg twice daily (2.2, 14.2)
JRA: 50 mg twice daily in patients 10–25 kg. 100 mg twice daily in patients more than 25 kg (2.3, 14.3)
AS: 200 mg once daily single dose or 100 mg twice daily. If no effect is observed after 6 weeks, a trial of 400 mg (single or divided doses) may be of benefit (2.4, 14.4)
AP and PD: 400 mg initially, followed by 200 mg dose if needed on first day. On subsequent days, 200 mg twice daily as needed (2.5, 14.5)
Reduce daily dose by 50% in patients with moderate hepatic impairment (Child-Pugh Class B).
Consider a dose reduction by 50% (or alternative management for JRA) in patients who are known or suspected to be CYP2C9 poor metabolizers, (2.6, 8.4, 8.8, 12.3).
For relief of the signs and symptoms of OA the recommended oral dose is 200 mg per day administered as a single dose or as 100 mg twice daily.
2.2 Rheumatoid Arthritis
For relief of the signs and symptoms of RA the recommended oral dose is 100 to 200 mg twice daily.
2.3 Juvenile Rheumatoid Arthritis
For the relief of the signs and symptoms of JRA the recommended oral dose for pediatric patients is based on weight. For patients ≥10 kg to ≤25 kg the recommended dose is 50 mg twice daily. For patients >25 kg the recommended dose is 100 mg twice daily.
For patients who have difficulty swallowing capsules, the contents of a Dolcelox capsule can be added to applesauce. The entire capsule contents are carefully emptied onto a level teaspoon of cool or room temperature applesauce and ingested immediately with water. The sprinkled capsule contents on applesauce are stable for up to 6 hours under refrigerated conditions (2–8° C/ 35–45° F).
2.4 Ankylosing Spondylitis
For the management of the signs and symptoms of AS, the recommended dose of Dolcelox is 200 mg daily in single (once per day) or divided (twice per day) doses. If no effect is observed after 6 weeks, a trial of 400 mg daily may be worthwhile. If no effect is observed after 6 weeks on 400 mg daily, a response is not likely and consideration should be given to alternate treatment options.
2.5 Management of Acute Pain and Treatment of Primary Dysmenorrhea
The recommended dose of Dolcelox is 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily as needed.
2.6 Special Populations
Hepatic insufficiency: The daily recommended dose of Dolcelox capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be reduced by 50%. The use of Dolcelox in patients with severe hepatic impairment is not recommended [see Warnings and Precautions (5.5), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Poor Metabolizers of CYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered Dolcelox with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e. CYP2C9*3/*3). Consider using alternative management in JRA patients who are poor metabolizers. [see Use in Specific populations (8.8), and Clinical Pharmacology (12.5)].
3. DOSAGE FORMS AND STRENGTHS
Capsules: 50 mg, 100 mg, 200 mg and 400 mg
Capsules: 50 mg, 100 mg, 200 mg and 400 mg (3)
Dolcelox is contraindicated:
In patients with known hypersensitivity to Dolcelox, aspirin, or other NSAIDs.
In patients who have demonstrated allergic-type reactions to sulfonamides.
In patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe anaphylactoid reactions to NSAIDs, some of them fatal, have been reported in such patients [see Warnings and Precautions (5.7, 5.13) ].
For the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1) ].
In patients with active gastrointestinal bleeding. [see Warnings and Precautions (5.4) ].
Known hypersensitivity to Dolcelox or sulfonamides (4)
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4, 5.7, 5.8, 5.13)
Use during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1)
Active gastrointestinal bleeding (4, 5.4)
5. WARNINGS AND PRECAUTIONS
Serious and potentially fatal cardiovascular thrombotic events, myocardial infarction, and stroke. Patients with known CV disease/risk factors may be at greater risk (5.1, 14.6, 17.2).
Serious gastrointestinal (GI) adverse events, which can be fatal. The risk is greater in patients with a prior history of ulcer disease or GI bleeding, and in patients at high risk for GI events, especially the elderly. Dolcelox should be used with caution in these patients (5.4, 8.5, 14.6, 17.3).
Elevated liver enzymes and, rarely, severe hepatic reactions. Discontinue use of Dolcelox immediately if abnormal liver enzymes persist or worsen (5.5, 17.4).
New onset or worsening of hypertension. Blood pressure should be monitored closely during treatment with Dolcelox (5.2, 7.4, 17.2).
Fluid retention and edema. Dolcelox should be used with caution in patients with fluid retention or heart failure (5.3, 17.6).
Renal papillary necrosis and other renal injury with long term use. Use Dolcelox with caution in the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics, ACE-inhibitors, or angiotensin II antagonists (5.6, 7.4, 8.7, 17.6).
Anaphylactoid reactions. Do not use Dolcelox in patients with the aspirin triad (5.7, 10, 17.7).
Serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal and can occur without warning even without known prior sulfa allergy. Discontinue Dolcelox at first appearance of rash or skin reactions (5.8, 17.5).
5.1 Cardiovascular Thrombotic Events
Chronic use of Dolcelox may cause an increased risk of serious adverse cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. In the APC (Adenoma Prevention with Dolcelox) trial, the hazard ratio for the composite endpoint of cardiovascular death, MI, or stroke was 3.4 (95% CI 1.4 – 8.5) for Dolcelox 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with Dolcelox 200 mg twice daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both Dolcelox dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [see Clinical Studies (14.6) ].
All NSAIDs, both COX-2 selective and non-selective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with Dolcelox, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV toxicity 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 Dolcelox does increase the risk of serious GI events [see Warnings and Precautions (5.4) ].
Two large, controlled, clinical trials of a different 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 [see Contraindications (4) ].
As with all NSAIDs, Dolcelox can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Dolcelox, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with Dolcelox and throughout the course of therapy. The rates of hypertension from the CLASS trial in the Dolcelox, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%, respectively [see Clinical Studies ].
5.3 Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs, including Dolcelox [see Adverse Reactions (6.1) ]. In the CLASS study [see Clinical Studies (14.6) ], the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on Dolcelox 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. Dolcelox should be used with caution in patients with fluid retention or heart failure.
5.4 Gastrointestinal Effects
Risk of GI Ulceration, Bleeding, and Perforation
NSAIDs, including Dolcelox, can cause serious gastrointestinal events including bleeding, ulceration, and perforation of the 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 NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. 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 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 (14.6) ]. With longer duration of use of NSAIDs, there is a trend for increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest duration consistent with individual patient treatment goals. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during Dolcelox therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.
Dolcelox is contraindicated in patients with active GI bleeding.
5.5 Hepatic Effects
Borderline elevations of one or more liver-associated enzymes may occur in up to 15% of patients taking NSAIDs, and notable elevations of ALT or AST have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs, including Dolcelox [see Adverse Reactions (6.1) ]. In controlled clinical trials of Dolcelox, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for Dolcelox and 5% for placebo, and approximately 0.2% of patients taking Dolcelox and 0.3% of patients taking placebo had notable elevations of ALT and AST.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with Dolcelox. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Dolcelox should be discontinued.
5.6 Renal Effects
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, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors, angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Clinical trials with Dolcelox have shown renal effects similar to those observed with comparator NSAIDs.
No information is available from controlled clinical studies regarding the use of Dolcelox in patients with advanced renal disease. Therefore, treatment with Dolcelox is not recommended in these patients with advanced renal disease. If Dolcelox therapy must be initiated, close monitoring of the patient's renal function is advisable.
5.7 Anaphylactoid Reactions
As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to Dolcelox. In post-marketing experience, rare cases of anaphylactic reactions and angioedema have been reported in patients receiving Dolcelox. Dolcelox should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications, Warnings and Precautions (5.7) ]. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
5.8 Skin Reactions
Dolcelox is a sulfonamide and can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events can occur without warning and in patients without prior known sulfa allergy. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
In late pregnancy, starting at 30 weeks gestation, Dolcelox should be avoided because it may cause premature closure of the ductus arteriosus [see Use in Specific Populations ].
5.10 Corticosteroid Treatment
Dolcelox cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
5.11 Hematological Effects
Anemia is sometimes seen in patients receiving Dolcelox. In controlled clinical trials the incidence of anemia was 0.6% with Dolcelox and 0.4% with placebo. Patients on long-term treatment with Dolcelox should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. Dolcelox does not generally affect platelet counts, prothrombin time, or partial thromboplastin time (PTT), and does not inhibit platelet aggregation at indicated dosages [see Clinical Pharmacology (12.2) ].
5.12 Disseminated Intravascular Coagulation (DIC)
Dolcelox should be used only with caution in pediatric patients with systemic onset JRA due to the risk of disseminated intravascular coagulation.
5.13 Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Dolcelox should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
5.14 Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, Dolcelox should be discontinued.
In controlled clinical trials, elevated BUN occurred more frequently in patients receiving Dolcelox 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.
The pharmacological activity of Dolcelox in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions.
5.16 Concomitant NSAID Use
The concomitant use of Dolcelox with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.
6. ADVERSE REACTIONS
Of the celecoxib-treated patients in the pre-marketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of Dolcelox of 200 mg or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received Dolcelox at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Most common adverse reactions in arthritis trials (>2% and >placebo): abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, rash (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Greenstone LLC Professional Information Services at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1 Pre-marketing Controlled Arthritis Trials
Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving Dolcelox from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence.
CBX = Dolcelox 100 – 200 mg twice daily or 200 mg once daily;
NAP = Naproxen 500 mg twice daily;
DCF = Diclofenac 75 mg twice daily;
IBU = Ibuprofen 800 mg three times daily.
Body as a whole
Central, Peripheral Nervous system
Upper Respiratory Infection
In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving Dolcelox and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the Dolcelox treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of Dolcelox patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain.
The following adverse reactions occurred in 0.1 – 1.9% of patients treated with Dolcelox (100 – 200 mg twice daily or 200 mg once daily):
Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on Dolcelox 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with Dolcelox was maintained with or without ASA use [see Clinical Pharmacology (12.2) ].
Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for Dolcelox, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively).
6.3 Juvenile Rheumatoid Arthritis Study
In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with Dolcelox or naproxen; 77 JRA patients were treated with Dolcelox 3 mg/kg BID, 82 patients were treated with Dolcelox 6 mg/kg BID, and 83 patients were treated with naproxen 7.5 mg/kg BID. The most commonly occurring (≥5%) adverse events in Dolcelox treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea and vomiting. The most commonly occurring (≥5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, Dolcelox at doses of 3 and 6 mg/kg BID had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups.
In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with Dolcelox 6 mg/kg BID. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged.
All Doses Twice Daily
System Organ Class
Abdominal pain NOS
Abdominal pain upper
Injury and Poisoning
InvestigationsAbnormal laboratory tests, which include: Prolonged activated partial thromboplastin time, Bacteriuria NOS present, Blood creatine phosphokinase increased, Blood culture positive, Blood glucose increased, Blood pressure increased, Blood uric acid increased, Hematocrit decreased, Hematuria present, Hemoglobin decreased, Liver function tests NOS abnormal, Proteinuria present, Transaminase NOS increased, Urine analysis abnormal NOS
Dizziness (excl vertigo)
Skin & Subcutaneous
6.4 Other Pre-Approval Studies
Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with Dolcelox in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RAstudies.
Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with Dolcelox in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of Dolcelox were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis in the post-oral surgery pain studies.
6.5 The APC and PreSAP Trials
Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to Dolcelox in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years [see Special Studies Adenomatous Polyp Prevention Studies (14.6) ].
Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from Dolcelox pre-marketing controlled arthritis trials , above). The adverse reactions for which these differences in patients treated with Dolcelox were greater as compared to the arthritis pre-marketing trials were as follows:
(400 to 800 mg daily)
N = 2285
Gastroesophageal reflux disease
The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking Dolcelox, at an incidence greater than placebo in the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies:
Concomitant use of Dolcelox and warfarin may result in increased risk of bleeding complications.
Concomitant use of Dolcelox increases lithium plasma levels. (7.2)
Concomitant use of Dolcelox may reduce the antihypertensive effect of ACE Inhibitors and angiotensin II antagonists. Concomitant use of Dolcelox with ACE-Inhibitors in elderly or volume depleted or renally compromised patients may result in deterioration of renal function, including acute renal failure. (7.4)
Use caution with drugs known to inhibit P450 2C9 or metabolized by 2D6 due to the potential for increased plasma levels (2.6, 8.4, 8.8, 12.3)
General: Dolcelox metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of Dolcelox with drugs that are known to inhibit CYP2C9 should be done with caution. Significant interactions may occur when Dolcelox is administered together with drugs that inhibit CYP2C9.
In vitro studies indicate that Dolcelox, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6.
Anticoagulant activity should be monitored, particularly in the first few days, after initiating or changing Dolcelox therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding complications. The effect of Dolcelox on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily 2–5 mg doses of warfarin. In these subjects, Dolcelox did not alter the anticoagulant effect of warfarin as determined by prothrombin time. However, in post-marketing experience, serious bleeding events, some of which were fatal, have been reported, predominantly in the elderly, in association with increases in prothrombin time in patients receiving Dolcelox concurrently with warfarin.
In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with Dolcelox 200 mg twice daily as compared to subjects receiving lithium alone. Patients on lithium treatment should be closely monitored when Dolcelox is introduced or withdrawn.
Dolcelox can be used with low-dose aspirin. However, concomitant administration of aspirin with Dolcelox increases the rate of GI ulceration or other complications, compared to use of Dolcelox alone [see Warnings and Precautions and Clinical Studies (14.6) ]. Because of its lack of platelet effects, Dolcelox is not a substitute for aspirin for cardiovascular prophylaxis [see Clinical Pharmacology (12.2) ].
7.4 ACE-inhibitors and Angiotensin II Antagonists
Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors and angiotensin II antagonists. This interaction should be given consideration in patients taking Dolcelox concomitantly with ACE-inhibitors and angiotensin II antagonists [see Clinical Pharmacology (12.2 ].
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, may result in deterioration of renal function, including possible acute renal failure. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in Dolcelox plasma concentration. This increase is due to the inhibition of Dolcelox metabolism via P450 2C9 by fluconazole [see Clinical Pharmacology ]. Dolcelox should be introduced at the lowest recommended dose in patients receiving fluconazole.
Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.
In an interaction study of rheumatoid arthritis patients taking methotrexate, Dolcelox did not have an effect on the pharmacokinetics of methotrexate [see Clinical Pharmacology ].
7.8 Concomitant NSAID Use
The concomitant use of Dolcelox with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.
8. USE IN SPECIFIC POPULATIONS
Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation
Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward.
Teratogenic effects: Dolcelox at oral doses ≥150 mg/kg/day (approximately 2-fold 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 Dolcelox at oral doses ≥30 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily) throughout organogenesis. There are no studies in pregnant women. Dolcelox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic effects: Dolcelox produced pre-implantation and post-implantation losses and reduced embryo/fetal survival in rats at oral dosages ≥50 mg/kg/day (approximately 6-fold human exposure based on the AUC0–24 at 200 mg twice daily). These changes are expected with inhibition of prostaglandin synthesis and are not the result of permanent alteration of female reproductive function, nor are they expected at clinical exposures. No studies have been conducted to evaluate the effect of Dolcelox on the closure of the ductus arteriosus in humans. Therefore, use of Dolcelox during the third trimester of pregnancy should be avoided.
8.2 Labor and Delivery
Dolcelox produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats. The effects of Dolcelox on labor and delivery in pregnant women are unknown.
8.3 Nursing Mothers
Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of Dolcelox in breast milk. The calculated average daily infant dose was 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. Caution should be exercised when Dolcelox is administered to a nursing woman.
8.4 Pediatric Use
Dolcelox is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to Dolcelox has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to Dolcelox or other COX-2 selective and non-selective NSAIDs [, and Clinical Studies (14.3) ].
The use of Dolcelox in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. Dolcelox has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both Dolcelox and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). NSAIDs including Dolcelox should be used only with caution in patients with systemic onset JRA, due to the risk of disseminated intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests [see Dosage and Administration (2.3), Warnings and Precautions (5.12), Adverse Reactions (6.3), Animal Toxicology (13.2), Clinical Studies (14.3) ].
Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers [see Poor Metabolizers of CYP2C9 substrates (8.8) ].
8.5 Geriatric Use
Of the total number of patients who received Dolcelox 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 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 (5.4, 5.6) ].
8.6 Hepatic Insufficiency
The daily recommended dose of Dolcelox capsules in patients with moderate hepatic impairment should be reduced by 50%. The use of Dolcelox in patients with severe hepatic impairment is not recommended [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ].
8.7 Renal Insufficiency
Dolcelox is not recommended in patients with severe renal insufficiency [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) ].
8.8 Poor Metabolizers of CYP2C9 Substrates
Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered Dolcelox with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers (i.e., CYP2C9*3/*3). Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers. [see Dosage and Administration (2.6) and Clinical Pharmacology (12.5) ].
No overdoses of Dolcelox were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity. Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. No information is available regarding the removal of Dolcelox by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
Dolcelox 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; the chemical structure is as follows:
Dolcelox oral capsules contain either 50 mg, 100 mg, 200 mg or 400 mg of Dolcelox, together with inactive ingredients including: croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate.
12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Dolcelox is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Dolcelox is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2, and at therapeutic concentrations in humans, Dolcelox does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, Dolcelox reduced the incidence and multiplicity of tumors.
Platelets: In clinical trials using normal volunteers, Dolcelox at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, Dolcelox is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of Dolcelox on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of Dolcelox.
Fluid Retention: Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.
Absorption: Peak plasma levels of Dolcelox occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels and area under the curve (AUC) are roughly dose-proportional up to 200 mg BID; at higher doses there are less than proportional increases in Cmax and AUC . Absolute bioavailability studies have not been conducted. With multiple dosing, steady-state conditions are reached on or before Day 5. The pharmacokinetic parameters of Dolcelox in a group of healthy subjects are shown in Table 3.
Mean (%CV) PK Parameter Values
Effective t1/2, hr
Food Effects: When Dolcelox capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media.
Coadministration of Dolcelox with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma Dolcelox concentrations with a decrease of 37% in Cmax and 10% in AUC. Dolcelox, at doses up to 200 mg twice daily, can be administered without regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption.
In healthy adult volunteers, the overall systemic exposure (AUC) of Dolcelox was equivalent when Dolcelox was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or t1/2 after administration of capsule contents on applesauce [see Dosage and Administration (2) ].
Distribution: In healthy subjects, Dolcelox is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that Dolcelox binds primarily to albumin and, to a lesser extent, α1-acid glycoprotein. The apparent volume of distribution at steady state (Vss/F) is approximately 400 L, suggesting extensive distribution into the tissues. Dolcelox is not preferentially bound to red blood cells.
Metabolism: Dolcelox metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors.
Excretion: Dolcelox is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t1/2) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min.
Geriatric: At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, Dolcelox Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose [see Dosage and Administration (2.6) and Use in Specific Populations (8.5) ].
Pediatric: The steady state pharmacokinetics of Dolcelox administered as an investigational oral suspension was evaluated in 152 JRA patients 2 years to 17 years of age weighing ≥10 kg with pauciarticular or polyarticular course JRA and in patients with systemic onset JRA. Population pharmacokinetic analysis indicated that the oral clearance (unadjusted for body weight) of Dolcelox increases less than proportionally to increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with a 70 kg adult RA patient.
Twice-daily administration of 50 mg capsules to JRA patients weighing ≥12 to ≤25 kg and 100 mg capsules to JRA patients weighing >25 kg should achieve plasma concentrations similar to those observed in a clinical trial that demonstrated the non-inferiority of Dolcelox to naproxen 7.5 mg/kg twice daily (see Dosage and Administration (2.3). Dolcelox has not been studied in JRA patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), or beyond 24 weeks.
Race: Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of Dolcelox in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown.
Hepatic Insufficiency: A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment has shown that steady-state Dolcelox AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, the daily recommended dose of Dolcelox capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of Dolcelox in patients with severe hepatic impairment is not recommended [see Dosage and Administration (2.6) and Use in Specific Populations (8.6) ].
Renal Insufficiency: In a cross-study comparison, Dolcelox AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35–60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and Dolcelox clearance. Patients with severe renal insufficiency have not been studied. Similar to other NSAIDs, Dolcelox is not recommended in patients with severe renal insufficiency [see Warnings and Precautions (5.6) ].
In vitro studies indicate that Dolcelox is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4.
In vivo studies have shown the following:
Lithium: In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg twice daily with Dolcelox 200 mg twice daily as compared to subjects receiving lithium alone [see Drug Interactions (7.2) ].
Fluconazole: Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in Dolcelox plasma concentration. This increase is due to the inhibition of Dolcelox metabolism via P450 2C9 by fluconazole [see Drug Interactions (7.5) ].
Other Drugs: The effects of Dolcelox on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, methotrexate [see Drug Interactions (7.7) ], phenytoin, and tolbutamide have been studied in vivo and clinically important interactions have not been found.
CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those 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 Dolcelox systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of Dolcelox have not been evaluated in subjects with other CYP2C9 polymorphisms, such as *2, *5, *6, *9 and *11. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups. [see Dosage and Administration (2.6), Use in Specific Populations (8.8) ].
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Dolcelox was not carcinogenic in rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females 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.
Dolcelox 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.
Dolcelox did not impair male and female fertility in rats at oral doses up to 600 mg/kg/day (approximately 11-fold human exposure at 200 mg twice daily based on the AUC0–24).
13.2 Animal Toxicology
An increase in the incidence of background findings of spermatocele with or without secondary changes such as epididymal hypospermia as well as minimal to slight dilation of the seminiferous tubules was seen in the juvenile rat. These reproductive findings while apparently treatment-related did not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous condition. Similar reproductive findings were not observed in studies of juvenile or adult dogs or in adult rats treated with Dolcelox. The clinical significance of this observation is unknown.
14. CLINICAL STUDIES
Dolcelox has demonstrated significant reduction in joint pain compared to placebo. Dolcelox was evaluated for treatment of the signs and the symptoms of OA of the knee and hip in placebo- and active-controlled clinical trials of up to 12 weeks duration. In patients with OA, treatment with Dolcelox 100 mg twice daily or 200 mg once daily resulted in improvement in WOMAC osteoarthritis index, a composite of pain, stiffness, and functional measures in OA. In three 12-week studies of pain accompanying OA flare, Dolcelox doses of 100 mg twice daily and 200 mg twice daily provided significant reduction of pain within 24–48 hours of initiation of dosing. At doses of 100 mg twice daily or 200 mg twice daily the effectiveness of Dolcelox was shown to be similar to that of naproxen 500 mg twice daily. Doses of 200 mg twice daily provided no additional benefit above that seen with 100 mg twice daily. A total daily dose of 200 mg has been shown to be equally effective whether administered as 100 mg twice daily or 200 mg once daily.
14.2 Rheumatoid Arthritis
Dolcelox has demonstrated significant reduction in joint tenderness/pain and joint swelling compared to placebo. Dolcelox was evaluated for treatment of the signs and symptoms of RA in placebo- and active-controlled clinical trials of up to 24 weeks in duration. Dolcelox was shown to be superior to placebo in these studies, using the ACR20 Responder Index, a composite of clinical, laboratory, and functional measures in RA. Dolcelox doses of 100 mg twice daily and 200 mg twice daily were similar in effectiveness and both were comparable to naproxen 500 mg twice daily.
Although Dolcelox 100 mg twice daily and 200 mg twice daily provided similar overall effectiveness, some patients derived additional benefit from the 200 mg twice daily dose. Doses of 400 mg twice daily provided no additional benefit above that seen with 100–200 mg twice daily.
14.3 Juvenile Rheumatoid Arthritis
In a 12-week, randomized, double-blind active-controlled, parallel-group, multicenter, non-inferiority study, patients from 2 years to 17 years of age with pauciarticular, polyarticular course JRA or systemic onset JRA, received one of the following treatments: Dolcelox 3 mg/kg (to a maximum of 150 mg) twice daily; Dolcelox 6 mg/kg (to a maximum of 300 mg) twice daily; or naproxen 7.5 mg/kg (to a maximum of 500 mg) twice daily. The response rates were based upon the JRA Definition of Improvement greater than or equal to 30% (JRA DOI 30) criterion, which is a composite of clinical, laboratory, and functional measures of JRA. The JRA DOI 30 response rates at week 12 were 69%, 80% and 67% in the Dolcelox 3 mg/kg BID, Dolcelox 6 mg/kg BID, and naproxen 7.5 mg/kg BID treatment groups, respectively.
The efficacy and safety of Dolcelox for JRA have not been studied beyond six months. The long-term cardiovascular toxicity in children exposed to Dolcelox has not been evaluated and it is unknown if the long-term risk may be similar to that seen in adults exposed to Dolcelox or other COX-2 selective and non-selective NSAIDs [(see Boxed Warning, Warnings and Precautions (5.12) ].
14.4 Ankylosing Spondylitis
Dolcelox was evaluated in AS patients in two placebo- and active-controlled clinical trials of 6 and 12 weeks duration. Dolcelox at doses of 100 mg twice daily, 200 mg once daily and 400 mg once daily was shown to be statistically superior to placebo in these studies for all three co-primary efficacy measures assessing global pain intensity (Visual Analogue Scale), global disease activity (Visual Analogue Scale) and functional impairment (Bath Ankylosing Spondylitis Functional Index). In the 12-week study, there was no difference in the extent of improvement between the 200 mg and 400 mg Dolcelox doses in a comparison of mean change from baseline, but there was a greater percentage of patients who responded to Dolcelox 400 mg, 53%, than to Dolcelox 200 mg, 44%, using the Assessment in Ankylosing Spondylitis response criteria (ASAS 20). The ASAS 20 defines a responder as improvement from baseline of at least 20% and an absolute improvement of at least 10 mm, on a 0 to 100 mm scale, in at least three of the four following domains: patient global pain, Bath Ankylosing Spondylitis Functional Index, and inflammation. The responder analysis also demonstrated no change in the responder rates beyond 6 weeks.
14.5 Analgesia, including Primary Dysmenorrhea
In acute analgesic models of post-oral surgery pain, post-orthopedic surgical pain, and primary dysmenorrhea, Dolcelox relieved pain that was rated by patients as moderate to severe. Single doses [see Dosage and Administration ] of Dolcelox provided pain relief within 60 minutes.
14.6 Special Studies
Adenomatous Polyp Prevention Studies: Cardiovascular safety was evaluated in two randomized, double-blind, placebo-controlled, three year studies involving patients with Sporadic Adenomatous Polyps treated with Dolcelox: the APC trial (Adenoma Prevention with Dolcelox) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke with Dolcelox compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint (adjudicated):
In the APC trial, the hazard ratios compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4 – 8.5) with Dolcelox 400 mg twice daily and 2.8 (95% CI 1.1 – 7.2) with Dolcelox 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively, compared to 0.9% (6/679 subjects) with placebo treatment. The increases in both Dolcelox dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction.
In the PreSAP trial, the hazard ratio for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6 – 2.4) with Dolcelox 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively.
Clinical trials of other COX-2 selective and non-selective NSAIDs of up to three-years duration have shown an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. As a result, all NSAIDs are considered potentially associated with this risk.
Dolcelox Long-Term Arthritis Safety Study (CLASS): This was a prospective, long-term, safety outcome study conducted post-marketing in approximately 5,800 OA patients and 2,200 RA patients. Patients received Dolcelox 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for Dolcelox (n = 3,987) and diclofenac (n = 1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The primary endpoint of this outcome study was the incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction). Patients were allowed to take concomitant low-dose (≤ 325 mg/day) aspirin (ASA) for cardiovascular prophylaxis (ASA subgroups: Dolcelox, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of complicated ulcers between Dolcelox and the combined group of ibuprofen and diclofenac were not statistically significant.
Patients on Dolcelox and concomitant low-dose ASA (N=882) experienced 4-fold higher rates of complicated ulcers compared to those not on ASA (N=3105). The Kaplan-Meier rate for complicated ulcers at 9 months was 1.12% versus 0.32% for those on low-dose ASA and those not on ASA, respectively [see Warnings and Precautions (5.4) ].
The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with Dolcelox 400 mg twice daily are described in Table 4. Table 4 also displays results for patients less than or greater than 65 years of age. The difference in rates between Dolcelox alone and Dolcelox with ASA groups may be due to the higher risk for GI events in ASA users.
Celecoxib alone (n=3105)
Celecoxib with ASA (n=882)
Patients <65 Years
Celecoxib alone (n=2025)
Celecoxib with ASA (n=403)
Patients ≥65 Years
Celecoxib alone (n=1080)
Celecoxib with ASA (n=479)
In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking Dolcelox alone or Dolcelox with ASA were, respectively, 2.56% (n=243) and 6.85% (n=91) at 48 weeks. These results are to be expected in patients with a prior history of ulcer disease [see Warnings and Precautions (5.4) and Adverse Reactions (6.1) ].
Cardiovascular safety outcomes were also evaluated in the CLASS trial. Kaplan-Meier cumulative rates for investigator-reported serious cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the Dolcelox, diclofenac, or ibuprofen treatment groups. The cumulative rates in all patients at nine months for Dolcelox, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial infarction in non-ASA users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a similar degree.
Endoscopic Studies: The correlation between findings of short-term endoscopic studies with Dolcelox and the relative incidence of clinically significant serious upper GI events with long-term use has not been established. Serious clinically significant upper GI bleeding has been observed in patients receiving Dolcelox in controlled and open-labeled trials [see Warnings and Precautions (5.4) and Clinical Studies (14.6) ]
A randomized, double-blind study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The incidence of endoscopic ulcers in patients taking Dolcelox 200 mg twice daily was 4% vs. 15% for patients taking diclofenac SR 75 mg twice daily. However, Dolcelox was not statistically different than diclofenac for clinically relevant GI outcomes in the CLASS trial [see Clinical Studies (14.6) ].
The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled studies in 2157 OA and RA patients in whom baseline endoscopies revealed no ulcers. There was no dose relationship for the incidence of gastroduodenal ulcers and the dose of Dolcelox (50 mg to 400 mg twice daily). The incidence for naproxen 500 mg twice daily was 16.2 and 17.6% in the two studies, for placebo was 2.0 and 2.3%, and for all doses of Dolcelox the incidence ranged between 2.7%–5.9%. There have been no large, clinical outcome studies to compare clinically relevant GI outcomes with Dolcelox and naproxen.
In the endoscopic studies, approximately 11% of patients were taking aspirin (≤ 325 mg/day). In the Dolcelox groups, the endoscopic ulcer rate appeared to be higher in aspirin users than in non-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic ulcer rates observed in the active comparator groups, with or without aspirin.
16. HOW SUPPLIED/STORAGE AND HANDLING
Dolcelox 50 mg capsules are white, with reverse printed white on red band of body and cap with markings of 7767 on the cap and 50 on the body, supplied as:
bottle of 60
Dolcelox 100 mg capsules are white, with reverse printed white on blue band of body and cap with markings of 7767 on the cap and 100 on the body, supplied as:
bottle of 100
bottle of 500
Dolcelox 200 mg capsules are white, with reverse printed white on gold band with markings of 7767 on the cap and 200 on the body, supplied as:
bottle of 100
bottle of 500
Dolcelox 400 mg capsules are white, with reverse printed white on green band with markings of 7767 on the cap and 400 on the body, supplied as:
bottle of 60
Storage: Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F)
17. PATIENT COUNSELING INFORMATION
Patients should be informed of the following information before initiating therapy with Dolcelox and periodically during the course of ongoing therapy.
17.1 Medication Guide
Patients should be informed of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and should be instructed to read the Medication Guide prior to using Dolcelox.
17.2 Cardiovascular Effects
Patients should be informed that Dolcelox may cause serious CV side effects such as MI or stroke, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to seek immediate medical advice if they observe any of these signs or symptoms. [see Warnings and Precautions ].
Patients should be informed that Dolcelox can lead to the onset of new hypertension or worsening of preexisting hypertension, and that Dolcelox may impair the response of some antihypertensive agents. Patients should be instructed on the proper follow up for monitoring of blood pressure. [see Warnings and Precautions (5.2) and Drug Interactions (7.4) ].
17.3 Gastrointestinal Effects
Patients should be informed that Dolcelox can cause gastrointestinal discomfort and more serious side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Patients should be informed of the signs and symptoms of ulcerations and bleeding, and to seek immediate medical advice if they observe any signs or symptoms that are indicative of these disorders, including epigastric pain, dyspepsia, melena, and hematemesis. [see Warnings and Precautions (5.4) ].
17.4 Hepatic Effects
Patients should be informed of the warning signs and symptoms of hepatotoxicity. Patients should be instructed that they should stop therapy and seek immediate medical therapy if these signs and symptoms occur [see Warnings and Precautions (5.5), Use in Specific Populations (8.6) ].
17.5 Adverse Skin Reactions
Patients should be informed that Dolcelox is a sulfonamide and can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be informed of the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and seek immediate medical advice when observing any indicative signs or symptoms.
Patients should be advised to stop Dolcelox immediately if they develop any type of rash and contact their physician as soon as possible.
Patients with prior history of sulfa allergy should not take Dolcelox [see Warnings and Precautions (5.8) ].
17.6 Weight Gain and Edema
Long-term administration of NSAIDs including Dolcelox has resulted in renal injury. Patients at greatest risk are those taking diuretics, ACE-inhibitors, angiotensin II antagonists, or with renal or liver dysfunction, heart failure, and the elderly [see Warnings and Precautions, Use in Specific Populations (8) ].
Patients should be instructed to promptly report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with Dolcelox [see Warnings and Precautions (5.3) ].
17.7 Anaphylactoid Reactions
Patients should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Patients should be instructed to seek immediate emergency assistance if they develop any of these signs and symptoms [see Warnings and Precautions (5.7) ].
17.8 Effects During Pregnancy
Patients should be informed that in late pregnancy Dolcelox should be avoided because it may cause premature closure of the ductus arteriosus [see Warnings and Precautions, Use in Specific Populations (8.1) ].
17.9 Preexisting Asthma
Patients should be instructed to tell their physicians if they have a history of asthma or aspirin-sensitive asthma because the use of NSAIDs in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Patients with this form of aspirin sensitivity should be instructed not to take Dolcelox. Patients with preexisting asthma should be instructed to seek immediate medical attention if their asthma worsens after taking Dolcelox [see Warnings and Precautions (5.13) ].
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.
This chance increases:
with longer use of NSAID medicines
in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:
can happen without warning symptoms
may cause death
The chance of a person getting an ulcer or bleeding increases with:
taking medicines called "corticosteroids" and "anticoagulants"
having poor health
NSAID medicines should only be used:
exactly as prescribed
at the lowest dose possible for your treatment
for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
different types of arthritis
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
for pain right before or after heart bypass surgery
Tell your healthcare provider:
about all of your medical conditions.
about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
Other side effects include:
high blood pressure
heart failure from body swelling (fluid retention)
kidney problems including kidney failure
bleeding and ulcers in the stomach and intestine
low red blood cells (anemia)
life-threatening skin reactions
life-threatening allergic reactions
liver problems including liver failure
asthma attacks in people who have asthma
Get emergency help right away if you have any of the following symptoms:
shortness of breath or trouble breathing
weakness in one part or side of your body
swelling of the face or throat
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:
more tired or weaker than usual
your skin or eyes look yellow
there is blood in your bowel movement or it is black and sticky like tar
skin rash or blisters with fever
unusual weight gain
swelling of the arms and legs, hands and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
Some of these NSAID medicines are sold in lower doses without a prescription (over –the –counter). Talk to your healthcare provider before using over –the –counter NSAIDs for more than 10 days.
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Lodine, Lodine XL
Nalfon, Nalfon 200
Motrin, Tab-Profen, VicoprofenVicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. (combined with hydrocodone), Combunox (combined with oxycodone)
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Dolcelox 200mg Capsule
Label Chemical Structure Logo
Dolcelox pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results. Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable. Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Capsules; Oral; Celecoxib 100 mg
Capsules; Oral; Celecoxib 200 mg
Dolcelox destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination. Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Cyclooxygenase-2 (COX-2) inhibitors
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Dolcelox Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug. Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Can i drive or operate heavy machine after consuming Dolcelox?
Depending on the reaction of the Dolcelox after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Dolcelox not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Dolcelox addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
sDrugs.com conducted a study on Dolcelox, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Dolcelox consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
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The information was verified by Dr. Arunabha Ray, MD Pharmacology