FELDENE- piroxicam_capsule
Function and Efficacy
Piroxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of FELDENE, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Piroxicam is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Piroxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because piroxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. General Pharmacokinetic Characteristics The pharmacokinetics of piroxicam have been characterized in healthy subjects, special populations and patients. The pharmacokinetics of piroxicam are linear. Proportional increase in exposure is observed with increasing doses. The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations throughout the day on once daily doses and significant accumulation upon multiple dosing. Most patients approximate steady state plasma levels within 7 to 12 days. Higher levels, which approximate steady state at two to three weeks, have been observed in patients in whom longer plasma half-lives of piroxicam occurred. Absorption Piroxicam is well absorbed following oral administration. Drug plasma concentrations are proportional for 10 mg and 20 mg doses and generally peak within three to five hours after administration. A single 20 mg dose generally produces peak piroxicam plasma levels of 1. 5 mcg/mL to 2 mcg/mL, while maximum drug plasma concentrations, after repeated daily administration of 20 mg piroxicam, usually stabilize at 3 mcg/mL to 8 mcg/mL. With food there is a slight delay in the rate but not the extent of absorption following oral administration. The concomitant administration of antacids (aluminum hydroxide or aluminum hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of orally administered piroxicam. Distribution The apparent volume of distribution of piroxicam is approximately 0. Ninety nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long term conditions (52 days). Piroxicam appeared in breast milk at approximately 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment. Elimination Metabolism Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the 5'-hydroxy-piroxicam, the major metabolite [see Clinical Pharmacology (12. 5) Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms compared to normal metabolizer type subjects [see Clinical Pharmacology (12. 5) Excretion Piroxicam and its biotransformation products are excreted in urine and feces, with about twice as much appearing in the urine as in the feces. Approximately 5% of a FELDENE dose is excreted unchanged. The plasma half-life (t ½ Specific Populations Pediatric Piroxicam has not been investigated in pediatric patients. Race Pharmacokinetic differences due to race have not been identified. Hepatic Impairment The effects of hepatic disease on piroxicam pharmacokinetics have not been established. However, a substantial portion of piroxicam elimination occurs by hepatic metabolism. Consequently, patients with hepatic disease may require reduced doses of piroxicam as compared to patients with normal hepatic function. Renal Impairment Piroxicam pharmacokinetics have been investigated in patients with renal insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing adjustments. However, the pharmacokinetic properties of piroxicam in patients with severe renal insufficiency or those receiving hemodialysis are not known. Drug Interaction Studies Antacids Concomitant administration of antacids had no effect on piroxicam plasma levels. Aspirin When piroxicam was administered with aspirin, its protein binding was reduced, although the clearance of free FELDENE was not altered. Plasma levels of piroxicam were decreased to approximately 80% of their normal values when FELDENE was administered (20 mg/day) in conjunction with aspirin (3900 mg/day). The clinical significance of this interaction is not known [see Drug Interactions (7) CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous CYP2C9*3/*3 (n=1) genotypes showed 1. 3-fold higher piroxicam systemic levels, respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following administration of a single oral dose. The mean elimination half-life values of piroxicam for subjects with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1. 8-fold higher than subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous*3/*3 genotype is 0% to 1% in the population at large; however, frequencies as high as 5. 7% have been reported in certain ethnic groups. Poor Metabolizers of CYP2C9 Substrates:.
Indication
FELDENE is indicated: FELDENE is a nonsteroidal anti-inflammatory drug indicated for 1 1.
Usage and Dosage
Carefully consider the potential benefits and risks of FELDENE and other treatment options before deciding to use FELDENE. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5) After observing the response to initial therapy with FELDENE, the dose and frequency should be adjusted to suit an individual patient's needs. For the relief of rheumatoid arthritis and osteoarthritis, the dosage is 20 mg given orally once per day. If desired, the daily dose may be divided. Because of the long half-life of FELDENE, steady-state blood levels are not reached for 7 to 12 days. Therefore, although the therapeutic effects of FELDENE are evident early in treatment, there is a progressive increase in response over several weeks and the effect of therapy should not be assessed for two weeks. 2 2.
Label
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 12) Most common adverse reactions (incidence >2% from clinical trials) are: nausea, constipation, flatulence, abdominal pain, diarrhea, headache, dizziness, edema, rash. 1 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. 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. In patients taking FELDENE or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 10% of patients are: Cardiovascular System Digestive System Nervous System Skin and Appendages Special Senses Additional adverse experiences reported occasionally include: Cardiovascular System Digestive System Nervous System Special Senses The following adverse reactions have been identified during post approval use of FELDENE. 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. Body as a Whole Cardiovascular System Digestive System Hemic and Lymphatic System Hypersensitivity Metabolic and Nutritional Nervous System Respiratory System Skin and Appendages Special Senses Urogenital System Reproductive System and Breast Disorders.
Precautions
FELDENE is contraindicated in the following patients: [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 1) 4 4 4.
Special Population Medication
Infertility 8. 3 Risk Summary Use of NSAIDs, including FELDENE, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of FELDENE use between about 20 and 30 weeks of gestation, and avoid FELDENE use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations Data Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including FELDENE, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats and rabbits, there was no evidence of teratogenicity at exposures up to 5 and 10 times the maximum recommended human dose (MRHD), respectively. In rat studies with piroxicam, fetotoxicity (postimplantation loss) was observed at exposures 2 times the MRHD, and delayed parturition and an increased incidence of stillbirth were noted at doses equivalent to the MRHD of piroxicam. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as piroxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including FELDENE, can cause premature closure of the fetal ductus arteriosus ( see Data Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If FELDENE treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue FELDENE and follow up according to clinical practice ( see Data Labor or Delivery There are no studies on the effects of FELDENE during labor or delivery. In animal studies, NSAIDS, including piroxicam inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Pregnant rats administered piroxicam at 2, 5, or 10 mg/kg/day during the period of organogenesis (Gestation Days 6 to 15) demonstrated increased post-implantation losses with 5 and 10 mg/kg/day of piroxicam (equivalent to 2 and 5 times the MRHD, of 20 mg respectively, based on a mg/m 2 2 In a pre- and post-natal development study in which pregnant rats were administered piroxicam at 2, 5, or 10 mg/kg/day on Gestation Day 15 through delivery and weaning of offspring, reduced weight gain and death were observed in dams at 10 mg/kg/day (5 times the MRHD based on a mg/m 2 Risk Summary Limited data from 2 published reports that included a total of 6 breastfeeding women and 2 infants showed piroxicam is excreted in human milk at approximately 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in maternal plasma during treatment. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FELDENE and any potential adverse effects on the breastfed infant from the FELDENE or from the underlying maternal condition. Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including FELDENE, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including FELDENE, in women who have difficulties conceiving or who are undergoing investigation of infertility. FELDENE has not been investigated in pediatric patients. The safety and effectiveness of FELDENE have not been established. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.
Drug Interactions
See Table 1 Table 1: Clinically Significant Drug Interactions with Piroxicam Drugs That Interfere with Hemostasis Clinical Impact: Intervention: Monitor patients with concomitant use of FELDENE with anticoagulants (e. , warfarin), antiplatelet drugs (e. , aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5. 12) Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5. 2) Intervention: Concomitant use of FELDENE and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5. 12) ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: Intervention: [see Warnings and Precautions (5. 6) Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e. , furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of FELDENE with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5. 6) Digoxin Clinical Impact: The concomitant use of piroxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of FELDENE and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. Intervention: During concomitant use of FELDENE and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e. , neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of FELDENE and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of FELDENE and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of FELDENE and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of piroxicam with other NSAIDs or salicylates (e. , diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5. 2) Intervention: The concomitant use of piroxicam with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of FELDENE and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of FELDENE and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Highly Protein Bound Drugs Clinical Impact FELDENE is highly protein bound and, therefore, might be expected to displace other protein bound drugs. Intervention Physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on other highly protein bound drugs. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with FELDENE may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of FELDENE with corticosteroids for signs of bleeding [see Warnings and Precautions (5. 2) Drugs that Interfere with Hemostasis (e. warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]) 7 Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers 7 ACE Inhibitors and ARBs 7 Diuretics 7 Digoxin 7.
Other Information
OVERDOSAGE
Symptoms following acute NSAID overdoses have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1 5.2 5.4 5.6) Manage patients with symptomatic and supportive care following an acute NSAID overdose. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving. If gastric decontamination may be potentially beneficial to the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients. The long plasma half-life of piroxicam should be considered when treating an overdose with piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
NONCLINICAL TOXICOLOGY
Carcinogenesis Long-term animal studies have not been conducted to characterize the carcinogenic potential of piroxicam. Mutagenesis Piroxicam was not mutagenic in an Ames bacterial reverse mutation assay, or in a dominant lethal mutation assay in mice, and was not clastogenic in an in vivo chromosome aberration assay in mice. Impairment of Fertility Reproductive studies in which rats were administered piroxicam at doses of 2, 5, or 10 mg/kg/day (up to 5 times the MRHD of 20 mg based on mg/m 2.
CLINICAL STUDIES
In controlled clinical trials, the effectiveness of FELDENE has been established for both acute exacerbations and long term management of rheumatoid arthritis and osteoarthritis. The therapeutic effects of FELDENE are evident early in the treatment of both diseases with a progressive increase in response over several (8en dash12) weeks. Efficacy is seen in terms of pain relief and, when present, subsidence of inflammation. Doses of 20 mg/day FELDENE display a therapeutic effect comparable to therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal effects and tinnitus. FELDENE has been administered concomitantly with fixed doses of gold and corticosteroids. The existence of a "steroid sparing" effect has not been adequately studied to date.