DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
Nacoflar Tablets are non-steroidal anti-inflammatory drug indicated for:
1.1 Osteoarthritis (OA)
Nacoflar tablets are indicated for relief of the signs and symptoms of osteoarthritis [see CLINICAL STUDIES (14.1)].
1.2 Rheumatoid Arthritis
Nacoflar tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis [see CLINICAL STUDIES (14.1)].
2 DOSAGE AND ADMINISTRATION
Use the lowest effective dose for the shortest duration consistent with individual treatment goals for the individual patient.
2.1 General Instructions
Carefully consider the potential benefits and risks of Nacoflar tablets and other treatment options before deciding to use Nacoflar tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see WARNINGS AND PRECAUTIONS (5.4)].
After observing the response to initial therapy with Nacoflar tablets, adjust the dose to suit an individual patient's needs.
In adults, the maximum recommended daily oral dose of Nacoflar tablets are 15 mg regardless of formulation. In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended [see WARNINGS AND PRECAUTIONS (5.6), USE IN SPECIFIC POPULATIONS (8.7) AND CLINICAL PHARMACOLOGY (12.3)].
Nacoflar may be taken without regard to timing of meals.
For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of Nacoflar tablets is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
2.3 Rheumatoid Arthritis
For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of Nacoflar tablets is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
3 DOSAGE FORMS AND STRENGTHS
4.1 Allergic Reactions
Nacoflar Tablets are contraindicated in patients with known hypersensitivity (e.g. anaphylactoid reactions and serious skin reactions) to Nacoflar. Nacoflar tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients [see WARNINGS AND PRECAUTIONS (5.7, 5.13)].
4.2 Coronary Surgery
Nacoflar tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see WARNINGS AND PRECAUTIONS (5.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years’ duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, 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 an NSAID, the lowest effective dose should be used for the shortest duration possible. 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 events and the steps to take if they occur.
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 [see CONTRAINDICATIONS (4.2)].
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 does increase the risk of serious GI events [see WARNINGS AND PRECAUTIONS (5.2)].
5.2 Gastrointestinal Effects - Risk of GI Ulceration, Bleeding, and Perforation
NSAIDs, including Nacoflar, can cause serious gastrointestinal (GI) adverse events including inflammation, 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. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs, occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, 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.
Prescribe NSAIDs, including Nacoflar, with extreme caution in those 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 for 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 in patients treated with an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during Nacoflar therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of Nacoflar until a serious GI adverse event is ruled out. For high-risk patients, consider alternate therapies that do not involve NSAIDs.
5.3 Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Nacoflar. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported [see ADVERSE REACTIONS (6.1)].
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Nacoflar. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Nacoflar [see USE IN SPECIFIC POPULATIONS (8.6) AND CLINICAL PHARMACOLOGY (12.3)].
NSAIDs, including Nacoflar, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. NSAIDs, including Nacoflar, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Patients taking ACE inhibitors, thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
5.5 Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. Use Nacoflar with caution in patients with fluid retention, hypertension, or heart failure.
5.6 Renal Effects
Long-term administration of NSAIDs, including Nacoflar, can result in renal papillary necrosis, renal insufficiency, acute renal failure, 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 a nonsteroidal anti-inflammatory drug 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, and angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
A pharmacokinetic study in patients with mild and moderate renal impairment revealed that no dosage adjustments in these patient populations are required. Patients with severe renal impairment have not been studied. The use of Nacoflar in patients with severe renal impairment with CrCl less than 20 mL/min is not recommended. A study performed in patients on hemodialysis revealed that although overall Cmax was diminished in this population, the proportion of free drug not bound to plasma was increased. Therefore it is recommended that Nacoflar dosage in this population not exceed 7.5 mg per day. Closely monitor the renal function of patients with impaired renal function who are taking Nacoflar [see DOSAGE AND ADMINISTRATION, USE IN SPECIFIC POPULATIONS (8.7) AND CLINICAL PHARMACOLOGY (12.3)].
Use caution when initiating treatment with Nacoflar in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Nacoflar. Caution is also recommended in patients with pre-existing kidney disease.
The extent to which metabolites may accumulate in patients with renal impairment has not been studied with Nacoflar. Because some Nacoflar metabolites are excreted by the kidney, monitor patients with significant renal impairment closely.
5.7 Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions have occurred in patients without known prior exposure to Nacoflar. Nacoflar 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 (4.1) AND WARNINGS AND PRECAUTIONS (5.12)]. Seek emergency help in cases where an anaphylactoid reaction occurs.
5.8 Adverse Skin Reactions
NSAIDs, including Nacoflar, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations and discontinue use of the drug at the first appearance of skin rash or any other sign of hypersensitivity.
Starting at 30 weeks gestation, avoid the use of Nacoflar, because it may cause premature closure of the ductus arteriosus [see USE IN SPECIFIC POPULATIONS (8.1) AND PATIENT COUNSELING INFORMATION (17.8)].
5.10 Corticosteroid Treatment
Nacoflar cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Slowly taper patients on prolonged corticosteroid therapy if a decision is made to discontinue corticosteroids.
5.11 Masking of Inflammation and Fever
The pharmacological activity of Nacoflar in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
5.12 Hematological Effects
Anemia may occur in patients receiving NSAIDs, including Nacoflar. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Nacoflar, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Carefully monitor patients treated with Nacoflar who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.
5.13 Use in Patients with Pre-existing 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 NSAIDs has been reported in such aspirin-sensitive patients, Nacoflar should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.
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 their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Nacoflar should be discontinued.
6 ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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 following serious adverse reactions are discussed elsewhere in the labeling:
6.1 Clinical Trials Experience
Osteoarthritis and Rheumatoid Arthritis
The Nacoflar Phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with Nacoflar 7.5 mg/day, 3,505 OA patients and 1351 RA patients treated with Nacoflar 15 mg/day. Nacoflar at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo- and/or active-controlled osteoarthritis trials and 2363 of these patients were treated in ten placebo- and/or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across Nacoflar trials.
A 12-week multicenter, double-blind, randomized trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of Nacoflar with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients with rheumatoid arthritis to compare the efficacy and safety of Nacoflar with placebo.
Table 1a depicts adverse events that occurred in ≥2% of the Nacoflar treatment groups in a 12-week placebo- and active-controlled osteoarthritis trial.
Table 1b depicts adverse events that occurred in ≥2% of the Nacoflar treatment groups in two 12-week placebo- controlled rheumatoid arthritis trials.
The adverse events that occurred with Nacoflar in ≥2% of patients treated short-term (4-6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 2
Higher doses of Nacoflar (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore, the daily dose of Nacoflar should not exceed 15 mg.
The following is a list of adverse drug reactions occurring in <2% of patients receiving Nacoflar in clinical trials involving approximately 16,200 patients.
6.2 Post Marketing Experience
The following adverse reactions have been identified during post approval use of Nacoflar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug. Adverse reactions reported in worldwide post marketing experience or the literature include: acute urinary retention; agranulocytosis; alterations in mood (such as mood elevation); anaphylactoid reactions including shock; erythema multiforme; exfoliative dermatitis; interstitial nephritis; jaundice; liver failure; Stevens-Johnson syndrome, and toxic epidermal necrolysis.
7 DRUG INTERACTIONS
See also Clinical Pharmacology (12.3).
NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking Nacoflar concomitantly with ACE-inhibitors.
When Nacoflar is administered with aspirin to healthy volunteers, an increase the AUC (10%) and Cmax (24%) of Nacoflar was noted. The clinical significance of this interaction is not known; however, as with other NSAIDs concomitant administration of Nacoflar and aspirin is not generally recommended because of the potential for increased adverse effects.
Concomitant administration of low-dose aspirin with Nacoflar may result in an increased rate of GI ulceration or other complications, compared to use of Nacoflar alone. Nacoflar is not a substitute for aspirin for cardiovascular prophylaxis.
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. However, studies with furosemide agents and Nacoflar have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of Nacoflar. Nevertheless, during concomitant therapy with Nacoflar, patients should be observed closely for signs of renal failure [see WARNINGS AND PRECAUTIONS (5.6)], as well as to ensure diuretic efficacy.
In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with Nacoflar 15 mg every day as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by Nacoflar. Closely monitor patients on lithium treatment for signs of lithium toxicity when Nacoflar is introduced, adjusted, or withdrawn.
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Therefore, NSAIDs may reduce the elimination of methotrexate, thereby enhancing the toxicity of methotrexate. Use caution when Nacoflar is administered concomitantly with methotrexate [see CLINICAL PHARMACOLOGY ].
Nacoflar, like other NSAIDs, may affect renal prostaglandins, thereby altering the renal toxicity of certain drugs. Therefore, concomitant therapy with Nacoflar may increase cyclosporine's nephrotoxicity. Use caution when Nacoflar is administered concomitantly with cyclosporine.
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Monitor anticoagulant activity, particularly in the first few days after initiating or changing Nacoflar therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding than with the use of either drug alone. Use caution when administering Nacoflar with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced [see CLINICAL PHARMACOLOGY (12.3)].
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C; Category D starting 30 weeks gestation.
There are no adequate and well-controlled studies in pregnant women. Nacoflar crosses the placental barrier. Prior to 30 weeks gestation, use Nacoflar during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, avoid Nacoflar and other NSAIDs, in pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, inform the patient of the potential hazard to a fetus [see WARNINGS AND PRECAUTIONS (5.9) AND PATIENT COUNSELING INFORMATION (17.8)]
Nacoflar was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the maximum recommended human daily dose [MRHD] based on body surface area [BSA] comparison). Administration of Nacoflar to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day. The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion).
In rats and rabbits, embryolethality occurred at oral Nacoflar doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65-and 6.5-fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis.
8.2 Labor and Delivery
The effects of Nacoflar on labor and delivery of pregnant women are unknown. Oral administration of Nacoflar to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at Nacoflar doses of 0.125 mg/kg/day or greater.
8.3 Nursing Mothers
It is not known whether this drug is excreted in human milk; however, Nacoflar was excreted in the milk of lactating rats at concentrations higher than those in plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nacoflar a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Use of this drug for a pediatric indication is protected by marketing exclusivity.
8.5 Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly.
Of the total number of subjects in clinical studies, 5157 were age 65 and over (4044 in OA studies and 1113 in RA studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Hepatic Impairment
No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Since Nacoflar is significantly metabolized in the liver, the use of Nacoflar in these patients should be done with caution [see WARNINGS AND PRECAUTIONS (5.3) AND CLINICAL PHARMACOLOGY (12.3)].
8.7 Renal Impairment
No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of Nacoflar in subjects with severe renal impairment is not recommended. Following a single dose of Nacoflar, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore it is recommended that Nacoflar dosage in this population not exceed 7.5 mg per day Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Nacoflar is not dialyzable [see DOSAGE AND ADMINISTRATION (2.1), WARNINGS AND PRECAUTIONS (5.6) AND CLINICAL PHARMACOLOGY (12.3)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
There is limited experience with Nacoflar overdose. Four cases have taken 6 to 11 times the highest recommended dose; all recovered. Cholestyramine is known to accelerate the clearance of Nacoflar.
Symptoms following acute NSAID overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular collapse, and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
Patients should be managed with symptomatic and supportive care following an NSAID overdose. Administration of activated charcoal is recommended for patients who present 1-2 hours after overdose. For substantial overdose or severely symptomatic patients, activated charcoal may be administered repeatedly. Accelerated removal of Nacoflar by 4 gm oral doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdose treatment, call a poison control center (1-800-222-1222).
Nacoflar, an oxicam derivative, is a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each yellow Nacoflar tablet contains 7.5 mg or 15 mg Nacoflar for oral administration. Nacoflar is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the following structural formula.
Nacoflar is a pale yellow powder, practically insoluble in water, slightly soluble in acetone, soluble in dimethylformamide, very slightly soluble in ethanol (96 %) and in methanol. Nacoflar has an apparent partition coefficient (log P)app = 0.1 in n-octanol/buffer pH 7.4. Nacoflar has pKa values of 1.1 and 4.2.
Each Nacoflar tablet intended for oral administration contains 7.5 mg or 15 mg of Nacoflar. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium citrate dihydrate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of Nacoflar, like that of other NSAIDs, may be related to prostaglandin synthetase inhibition which is involved in the initial steps of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin. It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy.
Nacoflar exhibits anti-inflammatory, analgesic, and antipyretic activities.
The absolute bioavailability of Nacoflar capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of Nacoflar capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean Cmax was achieved within four to five hours after a 7.5 mg Nacoflar tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady-state concentrations were reached by Day 5. A second Nacoflar concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling.
Food and Antacid Effects
Administration of Nacoflar capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., Cmax) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (Tmax) was achieved between 5 and 6 hours. In comparison, neither the AUC nor the Cmax values for Nacoflar suspension were affected following a similar high fat meal, while mean Tmax values were increased to approximately 7 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, Nacoflar can be administered without regard to timing of meals or concomitant administration of antacids.
The mean volume of distribution of Nacoflar is approximately 10 L. Nacoflar is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Nacoflar penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged Nacoflar.
Nacoflar concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.
Nacoflar is extensively metabolized in the liver. Nacoflar metabolites include 5'-carboxy Nacoflar (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl Nacoflar which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients’ peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. All the four metabolites are not known to have any in vivo pharmacological activity.
Nacoflar excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of Nacoflar, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of Nacoflar decreased the AUC of Nacoflar by 50%.
The mean elimination half-life (t1/2) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min.
Elderly males (≥ 65 years of age) exhibited Nacoflar plasma concentrations and steady-state pharmacokinetics similar to young males. Elderly females ( ≥ 65 years of age) had a 47% higher AUCss and 32% higher Cmax,ss as compared to younger females (≤ 55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients.
Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg Nacoflar, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or Tmax across genders.
Following a single 15 mg dose of Nacoflar there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of Nacoflar was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [see WARNINGS AND PRECAUTIONS (5.3) AND USE IN SPECIFIC POPULATIONS (8.6)].
Nacoflar pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of Nacoflar decreased and total clearance of Nacoflar increased with the degree of renal impairment while free AUC values were similar in all groups. The higher Nacoflar clearance in subjects with renal impairment may be due to increased fraction of unbound Nacoflar which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of Nacoflar in subjects with severe renal impairment is not recommended [see WARNINGS AND PRECAUTIONS (5.6) AND USE IN SPECIFIC POPULATIONS (8.7)].
Following a single dose of Nacoflar, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Nacoflar is not dialyzable [see DOSAGE AND ADMINISTRATION (2.1), WARNINGS AND PRECAUTIONS (5.6) AND USE IN SPECIFIC POPULATIONS (8.7)].
When Nacoflar is administered with aspirin (1000 mg three times daily) to healthy volunteers, it tended to increase the AUC (10%) and Cmax (24%) of Nacoflar. The clinical significance of this interaction is not known [see DRUG INTERACTIONS (7.2)].
Pretreatment for four days with cholestyramine significantly increased the clearance of Nacoflar by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for Nacoflar in the gastrointestinal tract. The clinical relevance of this interaction has not been established.
Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg Nacoflar.
Nacoflar 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and Nacoflar.
In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with Nacoflar 15 mg QD every day as compared to subjects receiving lithium alone [see DRUG INTERACTIONS (7.4)].
A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of Nacoflar on the pharmacokinetics of methotrexate taken once weekly. Nacoflar did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace Nacoflar from its human serum binding sites [see DRUG INTERACTIONS (7.5)].
The effect of Nacoflar on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, Nacoflar did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering Nacoflar with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced [see DRUG INTERACTIONS (7.7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no increase in tumor incidence in long-term carcinogenicity studies in rats and mice (99 weeks) administered Nacoflar at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.5- and 2.6-fold, respectively, the maximum recommended human daily dose based on body surface area comparison).
Nacoflar was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow.
Impairment of Fertility
Nacoflar did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 5.8- and 3.2-fold greater, respectively, than the maximum recommended human daily dose based on body surface area comparison).
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Osteoarthritis and Rheumatoid Arthritis
The use of Nacoflar for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a 12-week, double-blind, controlled trial. Nacoflar (3.75 mg, 7.5 mg, and 15 mg daily) was compared to placebo. The four primary endpoints were investigator’s global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function, and stiffness). Patients on Nacoflar 7.5 mg daily and Nacoflar 15 mg daily showed significant improvement in each of these endpoints compared with placebo.
The use of Nacoflar for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S. ranging from 4 weeks’ to 6 months’ duration. In these trials, the efficacy of Nacoflar, in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S. trial.
The use of Nacoflar for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a 12-week, double-blind, controlled multinational trial. Nacoflar (7.5 mg, 15 mg, and 22.5 mg daily) was compared to placebo. The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory, and functional measures of RA response. Patients receiving Nacoflar 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo. No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose.
16 HOW SUPPLIED/STORAGE AND HANDLING
Nacoflar Tablets, 7.5 mg are yellow, round-shaped, flat beveled edge, uncoated tablets debossed with ‘ZC’ and ‘25’ on one side and plain on other side and are supplied as follows:
Bottle of 15 – 68788-9898-1
Bottle of 20 - 68788-9898-2
Bottle of 30 - 68788-9898-3
Bottle of 60 - 68788-9898-6
Bottle of 100 - 68788-9898-0
Nacoflar Tablets, 15 mg are yellow, round-shaped, flat beveled edge, uncoated tablet debossed with ‘ZC’ and ‘26’ on one side and plain on other side and are supplied as follows:
Bottle of 15 - 68788-9897-1
Bottle of 20 - 68788-9897-2
Bottle of 30 - 68788-9897-3
Bottle of 60 - 68788-9897-6
Bottle of 100 - 68788-9897-0
Store at 20° to 25° C (68° to 77° F). Keep Nacoflar tablets in a dry place.
Dispense tablets in a tight container.
Keep this and all medications out of the reach of children.
17 PATIENT COUNSELING INFORMATION
See FDA-approved Medication Guide
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy.
17.1 Medication Guide
Inform patients of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and instruct them to read the Medication Guide prior to using Nacoflar tablets.
17.2 Cardiovascular Effects
NSAIDs including Nacoflar, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up [see WARNINGS AND PRECAUTIONS ].
17.3 Gastrointestinal Effects
NSAIDs including Nacoflar, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up [see WARNINGS AND PRECAUTIONS (5.2)].
Inform patients of the warning signs and symptoms of hepatotoxicity. If these occur, instruct patients to stop therapy and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS (5.3)].
17.5 Adverse Skin Reactions
NSAIDs, including Nacoflar, can cause serious skin side effects such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible [see WARNINGS AND PRECAUTIONS (5.8)].
17.6 Weight Gain and Edema
Advise patients to promptly report signs or symptoms of unexplained weight gain or edema to their physicians [see WARNINGS AND PRECAUTIONS ].
17.7 Anaphylactoid Reactions
Inform patients of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help [see WARNINGS AND PRECAUTIONS (5.7)].
17.8 Effects During Pregnancy
Starting at 30 weeks gestation, Nacoflar should be avoided as premature closure of the ductus arteriosus in the fetus may occur [see WARNINGS AND PRECAUTIONS (5.9) AND USE IN SPECIFIC POPULATIONS (8.1)].
Please address medical inquiries to, (MedicalAffairsNacoflarzydususa.com) Tel.: 1-877-993-8779.
Cadila Healthcare Ltd.
Zydus Pharmaceuticals USA Inc.
Pennington, NJ 08534
Revision Date : 29/04/2011
Relabeled By Preferred Pharmaceuticals, Inc
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:
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:
The chance of a person getting an ulcer or bleeding increases with:
NSAID medicines should only be used:
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:
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
Tell your healthcare provider:
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Get emergency help right away if you have any of the following symptoms:
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:
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 heartattack. 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 aprescription (over-the-counter). Talk to your healthcare provider before usingover-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
All registered trademarks in this document are the property of their respective owners.
Please address medical inquiries to, (MedicalAffairsNacoflarzydususa.com) Tel.: 1-877-993-8779.
This Medication Guide has been approved by the US Food and Drug Administration.
Cadila Healthcare Ltd.
Zydus Pharmaceuticals USA Inc.
Pennington, NJ 08534
Revision Date : 29/04/2011
Relabeled By Preferred Pharmaceuticals, Inc
Nacoflar 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.
Nacoflar available forms, composition, doses:
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.
Nacoflar 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.
Nacoflar 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.
Nacoflar pharmaceutical companies:
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.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Nacoflar?
Depending on the reaction of the Nacoflar after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Nacoflar 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 Nacoflar 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.
Reviewsdrugs.com conducted a study on Nacoflar, 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 Nacoflar 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.
Visitor reported usefulNo survey data has been collected yet
Visitor reported side effectsNo survey data has been collected yet
One visitor reported price estimatesWhat is your opinion about drug cost? Did you feel the cost is apt, or did you feel it is expensive?
The report given by the sdrugs.com website users shows the following figures about several people who felt the medicine Nacoflar is expensive, and the medicine is not expensive. The results are mixed. The perception of the cost of the medicine to be expensive or not depends on the brand name of the medicine, country, and place where it is sold, and the affordability of the patient. You can choose a generic drug in the place of the branded drug to save the cost. The efficiency of the medicine will not vary if it is generic or a branded one.
One visitor reported frequency of useHow often in a day do you take the medicine?
Are you taking the Nacoflar drug as prescribed by the doctor?
Few medications can be taken Once in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sdrugs.com website users about the frequency of taking the drug Nacoflar is mentioned below.
Elenen visitors reported dosesWhat is the dose of Nacoflar drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 11-50mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Two visitors reported time for resultsWhat is the time duration Nacoflar drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sdrugs.com website users needed 1 day to notice the result from using Nacoflar drug. The time needed to show improvement in health condition after using the medicine Nacoflar need not be same for all the users. It varies based on other factors.
Visitor reported administrationNo survey data has been collected yet
Three visitors reported age
The information was verified by Dr. Arunabha Ray, MD Pharmacology