Professional Drug Information > Indocin

Anti-inflammatory Drugs, Nonsteroidal (Systemic)

This monograph includes information on the following:

1) Diclofenac
2) Diflunisal
3) Etodolac  ^†
4) Fenoprofen
5) Floctafenine  ^*
6) Flurbiprofen
7) Ibuprofen
8) Indomethacin
9) Ketoprofen
10) Meclofenamate  ^†
11) Mefenamic Acid
12) Meloxicam
13) Nabumetone
14) Naproxen
15) Oxaprozin
16) Phenylbutazone
17) Piroxicam
18) Sulindac
19) Tenoxicam ^*
20) Tiaprofenic Acid ^*
21) Tolmetin

Note: See also individual Ketorolac (Systemic) monograph.
See also individual Meloxicam (Systemic) monograph.
See also Indomethacin—For Patent Ductus Arteriosus (Systemic) monograph.
See also Anti-inflammatory Agents, Nonsteroidal (Ophthalmic) monograph for information on ophthalmic use of diclofenac, flurbiprofen, and indomethacin.
See also Salicylates (Systemic) monograph for information on aspirin and other salicylates.



INN:
Etodolac  ^†—Etodolic acid.
Indomethacin—Indometacin.
Meclofenamate ^†—Meclofenamic acid.

BAN:
Meclofenamate ^†—Meclofenamic acid.


JAN:
Indomethacin—Indometacin.

VA CLASSIFICATION
Diclofenac
Primary: MS102
Secondary: CN104; MS400; CN105

Diflunisal
Primary: MS102
Secondary: CN104; MS400; CN105

Etodolac
Primary: MS102
Secondary: CN104; MS400; CN105

Fenoprofen
Primary: MS102
Secondary: CN104; MS400; CN105

Floctafenine
Primary: CN104
Secondary: CN105; MS400

Flurbiprofen
Primary: MS102

Ibuprofen
Primary: MS102
Secondary: CN104; CN850; MS400 ; CN105

Indomethacin
Primary: MS102
Secondary: MS400; CN850; CN105; CV900

Ketoprofen
Primary: MS102
Secondary: CN104; MS400; CN105

Meclofenamate
Primary: MS102
Secondary: CN104; CN105

Mefenamic Acid
Primary: CN104
Secondary: CN105

Meloxicam
Primary: MS102

Nabumetone
Primary: MS102

Naproxen
Primary: MS102
Secondary: CN104; CN850; MS400 ; CN105

Oxaprozin
Primary: MS102

Phenylbutazone
Primary: MS102
Secondary: MS400

Piroxicam
Primary: MS102
Secondary: MS400

Sulindac
Primary: MS102
Secondary: MS400

Tenoxicam
Primary: MS102

Tiaprofenic Acid
Primary: MS102

Tolmetin
Primary: MS102


Commonly used brand name(s): Actiprofen Caplets⁷; Actron⁹; Advil⁷; Advil Caplets⁷; Advil, Children's⁷; Albert Tiafen²⁰; Aleve¹⁴; Alka Butazolidin¹⁶; Anaprox¹⁴; Anaprox DS¹⁴; Ansaid⁶; Apo-Diclo¹; Apo-Diflunisal²; Apo-Flurbiprofen⁶; Apo-Ibuprofen⁷; Apo-Indomethacin⁸; Apo-Keto⁹; Apo-Keto-E⁹; Apo-Napro-Na¹⁴; Apo-Napro-Na DS¹⁴; Apo-Naproxen¹⁴; Apo-Phenylbutazone¹⁶; Apo-Piroxicam¹⁷; Apo-Sulin¹⁸; Apo-Tenoxicam¹⁹; Bayer Select Ibuprofen Pain Relief Formula Caplets⁷; Butazolidin¹⁶; Cataflam¹; Clinoril¹⁸; Cotylbutazone¹⁶; Cramp End⁷; Daypro¹⁵; Dolgesic⁷; Dolobid²; EC-Naprosyn¹⁴; Excedrin IB⁷; Excedrin IB Caplets⁷; Feldene¹⁷; Froben⁶; Froben SR⁶; Genpril⁷; Genpril Caplets⁷; Haltran⁷; Ibifon 600 Caplets⁷; Ibren⁷; Ibu⁷; Ibu-200⁷; Ibu-4⁷; Ibu-6⁷; Ibu-8⁷; Ibu-Tab⁷; Ibuprin⁷; Ibuprohm⁷; Ibuprohm Caplets⁷; Idarac⁵; Indocid⁸; Indocid SR⁸; Indocin⁸; Indocin SR⁸; Lodine³; Lodine XL³; Meclomen¹⁰; Medipren⁷; Medipren Caplets⁷; Midol IB⁷; Mobic¹²; Motrin⁷; Motrin Chewables⁷; Motrin, Children's⁷; Motrin, Children's Oral Drops⁷; Motrin, Junior Strength Caplets⁷; Motrin-IB⁷; Motrin-IB Caplets⁷; Nalfon⁴; Nalfon 200⁴; Naprelan¹⁴; Naprosyn¹⁴; Naprosyn-E¹⁴; Naprosyn-SR¹⁴; Naxen¹⁴; Novo-Difenac¹; Novo-Difenac SR¹; Novo-Diflunisal²; Novo-Flurprofen⁶; Novo-Keto-EC⁹; Novo-Methacin⁸; Novo-Naprox¹⁴; Novo-Naprox Sodium¹⁴; Novo-Naprox Sodium DS¹⁴; Novo-Pirocam¹⁷; Novo-Profen⁷; Novo-Sundac¹⁸; Novo-Tenoxicam¹⁹; Novo-Tolmetin²¹; Nu-Diclo¹; Nu-Flurbiprofen⁶; Nu-Ibuprofen⁷; Nu-Indo⁸; Nu-Naprox¹⁴; Nu-Pirox¹⁷; Nuprin⁷; Nuprin Caplets⁷; Orudis⁹; Orudis KT⁹; Orudis-E⁹; Orudis-SR⁹; Oruvail⁹; PMS-Piroxicam¹⁷; Pamprin-IB⁷; Ponstan¹¹; Ponstel¹¹; Q-Profen⁷; Relafen¹³; Rhodis⁹; Rhodis-EC⁹; Rufen⁷; Surgam²⁰; Surgam SR²⁰; Synflex¹⁴; Synflex DS¹⁴; Tolectin 200²¹; Tolectin 400²¹; Tolectin 600²¹; Tolectin DS²¹; Trendar⁷; Voltaren¹; Voltaren Rapide¹; Voltaren SR¹.

Other commonly used names are
Etodolic acid —Etodolac ^†
, Indometacin —Indomethacin
, Meclofenamic acid —Meclofenamate  ^†

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

^†Not commercially available in Canada.

Category:

Note: All of these medications have analgesic, antipyretic, and anti-inflammatory actions; however, indications for specific agents may vary because of lack of specific testing and/or clinical-use data as well as the toxicity of the individual nonsteroidal anti-inflammatory drug (NSAID). Clinically, most of these agents are used to treat a variety of painful and/or inflammatory conditions, both rheumatic and nonrheumatic, even though the specific uses are not listed in U.S. or Canadian product labeling. ^{225}



Antirheumatic (nonsteroidal anti-inflammatory)—Diclofenac; Diflunisal; Etodolac;  ^† Fenoprofen; Flurbiprofen; Ibuprofen; Indomethacin; Ketoprofen; Meclofenamate;  ^†Meloxicam; Nabumetone; Naproxen; Oxaprozin; Phenylbutazone; Piroxicam; Sulindac; Tenoxicam; Tiaprofenic Acid; Tolmetin;

Analgesic—Diclofenac; Diflunisal; Etodolac;  ^†Fenoprofen; Floctafenine; Ibuprofen; Ketoprofen; Meclofenamate;  ^† Mefenamic Acid; Naproxen;

Antigout agent—Diclofenac; Diflunisal; Etodolac;  ^†Fenoprofen; Floctafenine; Ibuprofen; Indomethacin; Ketoprofen; Naproxen; Phenylbutazone; Piroxicam; Sulindac;

Anti-inflammatory (nonsteroidal)— Flurbiprofen; Indomethacin; Naproxen; Sulindac; Tenoxicam;

Antipyretic—Ibuprofen; Indomethacin; Naproxen;

Antidysmenorrheal—Diclofenac; Flurbiprofen; Ibuprofen; Indomethacin; Ketoprofen; Meclofenamate;  ^† Mefenamic Acid; Naproxen; Piroxicam;

Vascular headache prophylactic— Fenoprofen; Ibuprofen; Indomethacin; Mefenamic Acid; Naproxen;

Vascular headache suppressant—Diclofenac; Diflunisal; Etodolac;  ^†Fenoprofen ; Floctafenine; Ibuprofen; Indomethacin; Ketoprofen; Meclofenamate;  ^†Mefenamic Acid; Naproxen;

Prostaglandin synthesis inhibitor, renal (Bartter"s syndrome)—Indomethacin ;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Rheumatic disease (treatment), such as
Arthritis, rheumatoid—Diclofenac, ^{{23} {158}} diflunisal, ^{{24} {165} {219}} fenoprofen, ^{{26} {27} {186} {187}} flurbiprofen, ^{{29} {126} {144} {169} {220}} ibuprofen, ^{{31} {38} {139} {181} {182} {183} {222}} indomethacin, ^{{32} {33} {175} {176}} ketoprofen, ^{{35} {36} {205} {206} {207}} meclofenamate, ^{{37} {178}} nabumetone, ^{{210} {211}} naproxen, ^{{01} {39} {40} {41} {142} {188} {189}} oxaprozin, ^{163} phenylbutazone¹ , ^{42} piroxicam, ^{{44} {45} {167} {168}} sulindac, ^{{46} {47} {160} {223}} tenoxicam, ^{180} tiaprofenic acid, ^{{48} {213}} and tolmetin ^{{49} {50} {215} {216}} are indicated for the treatment of acute or chronic rheumatoid arthritis.

Osteoarthritis—Diclofenac, ^{{23} {156} {158}} diflunisal, ^{{24} {25} {165} {219}} etodolac, ^{177} fenoprofen, ^{{26} {27} {186} {187}} flurbiprofen, ^{{29} {126} {144} {169} {220}} ibuprofen, ^{{31} {78} {139} {181} {182} {183} {222}} indomethacin, ^{{32} {33} {175} {176}} ketoprofen, ^{{35} {36} {205} {206} {207}} meclofenamate, ^{{37} {178}} meloxicam, ^{320} nabumetone, ^{211} naproxen, ^{{01} {39} {40} {41} {142} {188} {189}} oxaprozin, ^{163} phenylbutazone ¹ , ^{42} piroxicam, ^{{44} {45} {167} {168}} sulindac, ^{{46} {47} {160} {223}} tenoxicam, ^{180} tiaprofenic acid, ^{{48} {213}} and tolmetin ^{{49} {50} {215} {216}} are indicated for relief of acute or chronic osteoarthritis.

Ankylosing spondylitis—Diclofenac ¹, ^{{58} {158}} [ diflunisal]¹ , ^{233} [ fenoprofen]¹ , ^{233} [ flurbiprofen] , ^{{29} {126} {169} {220}} [ ibuprofen]¹ , ^{233} indomethacin, ^{{32} {33} {175} {176}} [ketoprofen] , ^{{36} {206} {207}} naproxen, ^{{01} {39} {40} {41} {142} {188} {189}} phenylbutazone, ^{{42} {43}} [piroxicam] , ^{{45} {168}} sulindac, ^{{46} {47} {160} {223}} tenoxicam, ^{180} and [tolmetin] ^{{50} {216}} are indicated for relief of acute or chronic ankylosing spondylitis.

Arthritis, juvenile—Ibuprofen, ^{{128} {129} {139}} indomethacin ¹ , ^{32} naproxen, ^{{01} {39} {41} {142} {188} {189}} and tolmetin ^{{49} {50} {215} {216}} are indicated for relief of acute or chronic juvenile arthritis.

[Arthritis, psoriatic]¹—Diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, phenylbutazone, and tolmetin are used in the treatment of psoriatic arthritis. ^{233}

[Reiter"s disease]¹—Indomethacin is used in the treatment of Reiter"s disease. ^{234}

[Rheumatic complications associated with Paget"s disease of bone]¹— Indomethacin is used in the treatment of this condition. ^{235}
Although NSAIDs may be required for relief of [ rheumatic complications occurring in association with systemic lupus erythematosus (SLE)]¹ , ^{{227} {236}} extreme caution is recommended because patients with SLE may be predisposed toward NSAID-induced central nervous system (CNS) and/or renal toxicity. ^{236} Several NSAIDs, including ibuprofen, ^{{103} {104} {105} {107}} sulindac, ^{109} and tolmetin, ^{108} have been shown to cause serious adverse effects, including aseptic meningitis, in patients with SLE. In addition, ibuprofen (although a causal relationship has not been established), ^{31} meclofenamate, ^{37} and phenylbutazone ^{43} have rarely been reported to cause an SLE-like syndrome and/or to exacerbate pre-existing SLE.

NSAIDs do not affect the progressive course of some forms of rheumatic disease. Some patients with rheumatoid arthritis may need additional treatment. ^{228}
Pain (treatment)—Diclofenac, ^{{158} {218}} diflunisal, ^{{24} {25} {165} {219}} etodolac, ^{177} fenoprofen¹ , ^{{26} {186}} floctafenine, ^{{28} {174}} ibuprofen, ^{{31} {78} {139} {181} {182} {183} {222}} ketoprofen, ^{{35} {205} {206}} meclofenamate, ^{{127} {178}} mefenamic acid, ^{{38} {79} {208} {209}} and naproxen ^{{01} {39} {41} {142} {143} {188} {226}} are indicated for relief of mild to moderate pain, especially when anti-inflammatory actions may also be desired, e.g., following dental, obstetric, or orthopedic surgery, and for relief of musculoskeletal pain due to soft tissue athletic injuries (strains or sprains). Only immediate-release dosage forms are recommended for relief of acute pain because of their more rapid onset of action relative to delayed-release or extended-release dosage forms. ^{240}
—Mefenamic acid is indicated for relief of mild to moderate pain when therapy will not exceed 1 week. ^{{38} {209}}
—Those NSAIDs indicated for relief of pain are also recommended for relief of mild to moderate bone pain caused by metastatic neoplastic disease. However, careful patient selection is necessary, especially in patients receiving chemotherapy, because of the potential gastrointestinal or renal toxicity and the platelet aggregation–inhibiting actions of these medications. ^{235}

Gouty arthritis, acute (treatment) or
[Calcium pyrophosphate deposition disease, acute (treatment)]^{1 {235}}—[Diclofenac]¹, ^{309} [diflunisal]¹ , ^{309} [etodolac] , ^{309} [fenoprofen]¹ , ^{237} floctafenine¹ , ^{309} [ibuprofen]¹ , ^{237} indomethacin, ^{{32} {33} {175} {176}} [ ketoprofen]¹ , ^{238} [ meclofenamate] , ^{309} [ mefenamic acid]¹ , ^{309} naproxen¹ , ^{{01} {142} {188}} phenylbutazone, ^{{42} {43} {224}} [piroxicam]¹ , ^{235} and sulindac ^{{46} {47} {160} {223}} are indicated [or used ] for relief of the pain and inflammation of acute gouty arthritis and [ acute calcium pyrophosphate deposition disease (pseudogout; chondrocalcinosis articularis; synovitis, crystal-induced)]¹ . Only immediate-release dosage forms are recommended for relief of acute attacks because of their more rapid onset of action relative to delayed-release or extended-release dosage forms. ^{240}
—[Long-term prophylactic use of an NSAID may decrease the incidence or severity of recurrent acute gout attacks, especially during the early months of antihyperuricemic therapy. ^{237} The NSAIDs do not correct hyperuricemia (although diclofenac, ^{158} diflunisal, ^{164} etodolac, ^{177} oxaprozin, ^{{253} {254}} and phenylbutazone ^{224} have some uricosuric activity) and do not eliminate the need for administration of an antihyperuricemic agent for the long-term management of chronic gout. ^{237} Colchicine is the recommended agent for preventing acute gout attacks because, in low (prophylactic) doses, it is less toxic for long-term use than NSAIDs. ^{229} NSAIDs (other than phenylbutazone, which is not recommended for long-term treatment) ^{237} should be used only for patients unable to tolerate even prophylactic doses of colchicine. ^{229}]

Inflammation, nonrheumatic (treatment)—Most of the NSAIDs are indicated [or used] in the treatment of painful nonrheumatic inflammatory conditions, such as
Athletic injuries
Bursitis
Capsulitis
Synovitis
Tendinitis; or
Tenosynovitis—[Flurbiprofen is indicated for relief of bursitis, tendinitis, and soft tissue injuries.] ^{{145} {220}} Indomethacin^{1 {32} {176}} and sulindac ^{{46} {47} {160} {223}} are indicated for treatment of bursitis and/or tendinitis of the shoulder. Naproxen ^{{01} {39} {142} {143} {188}} is indicated for treatment of bursitis and/or tendinitis of any joint. Tenoxicam is indicated for treatment of tendinitis, bursitis, and periarthritis of the shoulders or hips. ^{180} [Other NSAIDs, especially those approved by U.S. and/or Canadian regulatory agencies for relief of pain, are also used in the treatment of these and other painful inflammatory conditions.]^{1 {239}}

Fever (treatment)—Ibuprofen ^{{137} {139} {183}} and naproxen ^{1 {226}} are indicated for reduction of fever.

[Fever, due to malignancy (treatment) ]¹—Indomethacin (rapidly acting dosage forms only) is used to reduce fever in patients with Hodgkin"s disease, other lymphomas, and hepatic metastases of solid tumors. Indomethacin should be used only after aspirin and acetaminophen have proven ineffective. If antipyretic therapy at an adequate dosage is not effective within 48 hours, indomethacin should be discontinued. ^{234}

Dysmenorrhea (treatment)—Diclofenac, ^{{59} {158} {218}} [ flurbiprofen] , ^{{30} {169} {220}} ibuprofen, ^{{31} {78} {139} {181} {182} {183} {222}} [indomethacin ]¹ , ^{{07} {225}} ketoprofen, ^{{35} {205} {206}} meclofenamate, ^{178} mefenamic acid, ^{{38} {79} {108} {209}} naproxen, ^{{01} {39} {80} {142} {143} {188} {226}} and [piroxicam] ^{168} are indicated for relief of the pain and other symptoms of primary dysmenorrhea. [Other NSAIDs that have been approved by U.S. and/or Canadian regulatory agencies for relief of pain are also used to relieve dysmenorrhea.]^{1 {240}} Only immediate-release dosage forms are recommended for relief of dysmenorrhea because of their more rapid onset of action relative to delayed-release or extended-release dosage forms. ^{240}
—[Because of the high incidence of adverse effects with effective doses of indomethacin, ^{07} it is recommended that indomethacin be used only for severe primary dysmenorrhea unresponsive to other, less toxic, NSAIDs.] ^{241}

Hypermenorrhea (treatment)—Meclofenamate is indicated for treatment of idiopathic excessive menstrual bleeding. The absence of an underlying pathologic condition should be verified before meclofenamate therapy is instituted. ^{178} [NSAIDs that are used for relief of dysmenorrhea (see Dysmenorrhea , above) may also decrease excessive menstrual blood loss caused by an intrauterine device in addition to relieving other symptoms.]^{1 {07}}

[Headache, vascular (prophylaxis) ]¹or
[Headache, vascular (treatment)]¹—Diclofenac, diflunisal, etodolac, fenoprofen, floctafenine, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefenamic acid, and naproxen are used to relieve (when taken at the first sign of onset) migraine headache or other vascular headaches. Fenoprofen, ibuprofen, indomethacin, and naproxen are also used chronically to prevent recurrence of such headaches. Fenoprofen, ibuprofen, indomethacin, mefenamic acid, and naproxen may also be taken prior to and during menstruation to prevent migraine associated with menstruation. ^{242}

[Bartter"s syndrome (treatment)]¹—Indomethacin is used in the treatment of Bartter"s syndrome. However, its use in this condition has been associated with adverse effects, including pseudotumor cerebri. Because long-term therapy is required, it has been suggested that other, less toxic, NSAIDs may be suitable alternatives to indomethacin. ^{234}

[Pericarditis]¹—Indomethacin (rapidly acting dosage forms only) is used to relieve pain, fever, and inflammation associated with pericarditis. ^{240}

Unaccepted
Except in the treatment of ankylosing spondylitis, for which it is a treatment of choice, and Bartter"s syndrome, indomethacin is not recommended as initial therapy because of its potential for causing severe side effects. ^{176} Also, although indomethacin, like other NSAIDs, has analgesic and antipyretic activity, it should not be used indiscriminately (because of its toxicity) to relieve pain or reduce fever. ^{241}

Phenylbutazone is not recommended as initial therapy for any indication. Because of its potential for causing severe side effects, including agranulocytosis and aplastic anemia, it should be used only after less toxic treatments (including other, less toxic, NSAIDs) have been found ineffective. In many countries, phenylbutazone is approved only for treatment of severe ankylosing spondylitis unresponsive to other NSAIDs. Use of phenylbutazone to relieve the pain and inflammation of acute painful shoulder (i.e., peritendinitis, capsulitis, or bursitis of that joint) is no longer FDA-approved. It is strongly recommended that use of phenylbutazone be restricted to short-term treatment of severe flares of rheumatic disease, gout, or calcium pyrophosphate deposition disease. ^{{42} {43} {236}
1} Not included in Canadian product labeling.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics

Drug and Route	Absorption		% Protein- Binding * (Factors that decrease)	Plasma Concentration
	Rate (Factors that decrease)	Extent (Factors that decrease)		Time to Peak (hr) [dose in mg]	Peak (mcg/mL) [dose in mg]	Time to Steady-State (days) [dose in mg/ doses per day]	Steady-State (mcg/mL) [dose in mg/ doses per day]
Diclofenac			>99
Oral
Tablets	Rapid (food)	Complete		1, range 0.33–2 †; up to 3.6 ‡
Delayed-release Tablets	Rapid (food)	Complete		2, range 0.25–4 †; 6 ‡	0.7–1.1 [25] 1.5–1.6 [50] † 2 [75] Decreased 40% by food
Extended-release Tablets				4
Rectal	Rapid			0.5–2
Diflunisal			>99
Oral	Rapid (food)	Complete		2–3	41 [250] 87 [500] 124 [1000]		56 [250/2] 190 [500/2]
Etodolac			>99
Oral	Rapid (food) §	Extensive		1.3, range 0.8–1.8 †; 2.2–5.6 ‡ [200–600]; Steady-state 1.7±1.3	10–46 [200–600] Decreased 50% by food and 15–20% by antacids		16.5–19 [200/2]
Fenoprofen			99
Oral	Rapid (food, milk) §			1–2 [600] † Increased by food	50 [600] † Decreased by food
Floctafenine
Oral	Rapid (food)			1–2		Within 3
Flurbiprofen			99
Oral
Tablets	Rapid (food)			1.5; range 0.5–4	5–6; 8.7 # [50] 10–15 [100] ** Decreased by food		5–6 [50/3]
Extended-release Capsules				5.5 †; 8.3 ‡	8.56 Increased by food	2–3 [200/1]	10.78 [200/1]
Ibuprofen			99
Oral	Rapid (food) §			1.2–2.1	22–27 [200] 23–45 [400] 42–57 [600] †† 56–66 [800] Decreased up to 30% by food
Indomethacin			99
Oral
Capsules; Oral Suspension	Rapid (food, antacids [Al- and/or Mg- containing])	Complete; 90% in 4 hr		0.5–2 [25]	0.8–2.5 [25] 2.5–4 [50]		1.4 [25/3] 2.8 [50/3]
Extended-release
Capsules		90% in 12 hr		2–4.25 [75]	1.5–3 [75]		1.4 [75/1]
Rectal	Rapid	80–90 ‡‡
Ketoprofen			99 (hepatic cirrhosis, advanced age)			<1
Oral
Capsules	Rapid (food, milk) §	Complete		0.5–2 [50] average 1.1 † average 2 ‡	4.1 [50] † # 2.4 [50] ‡ #
Extended-release Capsules	Slow	Almost complete		6–7 †; 8–9 ‡	3.1±1.2 †; 3.4±1.3 ‡ [200]
Delayed-release Tablets	Delayed by ±1.5 hr			1.5–4 [50]
Extended-release Tablets				5.5–8	Decreased 20% by high-fat meal
Rectal §§				0.5–2
Meclofenamate			>99
Oral	Rapid (food) §	Complete (food)		0.5–2	8–9 [100]		4.8, range 1.8-7.2 [100/3] Decreased by food
Mefenamic Acid
Oral	Rapid			2.5 [250] 1–2 [500] 2–4 [1000]	3.6 [250] 3.5 [500] 10 [1000]	2 [1000/4]	20 [1000/4]
Meloxicam
Oral	Rapid	Extensive	>99	4 —5 [7.5]	1.05 [7.5]	5 [7.5/1]
Nabumetone (prodrug)
Oral	Increased by food, milk §	Increased by food, milk §
6-methoxy-2-naph- thylacetic acid (6-MNA) (active substance)			>99	Steady-state 3, range 1–12 [1000] ##; 2.5, range 1–8 [2000] Decreased by food	24 [500] ‡ 22–23 †; 36–38 ‡ # [1000] *** 64 [2000]	3 [500/2 or 1000/1]	18.5 [500/2]; trough 33, peak 52 [1000/1] #
Naproxen			>99 (hepatic cirrhosis, advanced age)
Oral
Tablets; Oral Suspension	Rapid (food, antacids [Al- and Mg- contain- ing]) †††	Complete		Naproxen: 2–4 [750] Sodium salt: 1–2 [825]	46.6 [375] 63.1 [500] ‡‡‡ 90 [750]	2–2.5 (500/2)	55 [500/2]
Delayed-release Tablets				4.2-4.5 Decreased by antacids Increased by high-fat meal	47.9 [375] 58.2 [2×250] 60.7 [500] §§§
Extended-release Tablets				9.7 †; 7.7 ‡ [1000]	63.1 †; 86.1 ‡ [1000]
Oxaprozin			±99.9(renal impairment, congestive heart failure, hepatic cirrhosis)
Oral	Relatively slow § (food–slight effect)			3-5	70-80 [1200]	4-7	98-230 [600/1 or 1200/1] Accumulates with chronic dosing
Phenylbutazone			98
Oral	Rapid			2–2.5	43 [300]		Phenylbuta- zone: up to 172 Oxyphenbuta- zone: up to 86
Piroxicam
Oral	(food) §			3–5 [20]	1.5–2 [20]	7–12 [20/1] ###	3–8 [20/1] ****
Rectal				10 [20]
Sulindac (prodrug)
Oral	(food) §	90%		2 † 3–4 ‡	1–2 [200]
Sulindac sulfide
(active substance)				1.7 ††††		4–5 [200/2]	4 [200/2]
Tenoxicam			98–99
Oral	(food) §	Extensive §		1.25, range 0.5–6 †	1.46–3.31 † [20]
Tiaprofenic Acid			98
Oral
Tablets	Rapid (food) §			0.5-1.5 † Up to 2 ‡	26 [200] 50 [300]	Within 1 [200/3]
Extended-release Capsules				Steady-state 4–8 [600/1]
Tolmetin			>99
Oral	Rapid (food) §	Almost complete (food, milk)		0.5–1	40 [400] † 20 [400] ‡

^* To albumin.
^† Taken on an empty stomach.
^‡  Taken with food.
^§ Absorption not affected by antacids, specifically: For fenoprofen, ibuprofen, ketoprofen, meclofenamate, piroxicam, sulindac, tolmetin—Aluminum- and magnesium-containing; For tiaprofenic acid—Aluminum-containing
^# May be increased in geriatric patients (For flurbiprofen, geriatric females only).
^** Decreased by 40% in patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis.
^†† Decrease to 37 mcg/mL demonstrated in obese patients, probably because volume of distribution increased.
^‡‡ Failure to retain suppository in rectum for one full hour may be responsible for incomplete absorption.
^§§ Bioavailability 73–93% of that achieved with oral administration.
^## Mean 8 hours in patients with hepatic cirrhosis. Not significantly different in geriatric patients than in younger adults.
^*** Administration of a second 1000-mg dose 12 hours after an initial 1000-mg dose produced peak concentrations of ±71 mcg/mL. Peak concentrations are significantly decreased (to as low as 18 mcg/mL) in patients with hepatic cirrhosis.
^†††  May be increased by concurrent administration of sodium bicarbonate.
^‡‡‡ Similar values reported with administration of 500-mg tablets to adults and with administration of 5 mg/kg of oral suspension to children 5 to 16 years of age with juvenile arthritis.
^§§§ Increased to 70.7 mcg/mL by concurrent administration with antacid.
^### May be increased to 2 to 3 weeks if elimination half-life is greatly prolonged.
^**** May be increased if elimination half-life is greatly prolonged and/or renal function is impaired.
^†††† May be increased to 4 to 7 hours in patients with alcoholic hepatic disease.

Table 2. Pharmacology/Pharmacokinetics

Drug	Biotransformation	Half-Life		Renal Elimination		Biliary/Fecal Elimination
		Distribution (hr)	Elimination (hr)	% of Dose	% Unchanged	% of Dose	% Unchanged
Diclofenac *	Hepatic; almost 50% eliminated via first-pass metabolism †		1.2–2	40–65	Little or none	35	Little or none
Diflunisal ‡			8–12 22 (GFR 10–50) § # 60 (GFR 2–10) § # 115 (GFR <2) § #	80–95 in 72–96 hr 53 in 72 hr (GFR 10–50) § 9.5 in 72 hr (GFR 2–10) § 2.7 in 72 hr (GFR <2) §	<5	Little or none
Etodolac ‡	Hepatic, extensive. No significant first-pass metabolism	0.71±0.5, at steady-state	Single dose 6–7; Steady-state 7.3±4	72; 60% in 24 h	<1	16
Fenoprofen	Hepatic		3	90 in 24 hr
Floctafenine	Hepatic; rapid	1	8	40 **		60 **
Flurbiprofen		3	5.7, range 2–12	88–98; 73 within 48 hr	20–25
Ibuprofen ‡	Hepatic		1.8–2	100 in 24 hr	<1
Indomethacin ‡	Hepatic	1	2.6–11.2 (average 4.5) ††	60	10–20	33 ‡‡	1.5
Ketoprofen *	Primarily hepatic; glucuronide conjugation may also occur in other tissues	0.33	Capsules 1.6; Extended-release Capsules 5.4±2.2; Extended-release Tablets 3–4 ##	80 in 24 hr	Up to 10	***
Meclofenamate	†††		2 (single dose) 3.3 (multiple doses)	66	Little or none	33
Mefenamic Acid	Hepatic		2	67		Up to 25
Meloxicam	Hepatic, mainly by cytochrome P-450 2C9		15 – 20	20	£ 0.5	20	1.6
Nabumetone	Hepatic, with extensive first-pass metabolism. 35–38% of a 1000-mg dose metabolized to the active substance 6-MNA, which is further metabolized hepatically; bioavailability of 6-MNA decreased in patients with severe hepatic function impairment		6-MNA: 23±3.7; 30±8.1 ‡‡‡	6-MNA: 80; 75 in 48 hr; complete in 168 hr; 32.5 in 96 hr §§§	6-MNA: <1
Naproxen	Hepatic		13	95
Oxaprozin ‡	Hepatic, 65% via microsomal oxidation followed by glucuronic acid conjugation and 35% via direct glucuronic acid conjugation		Steady- state (mg/day) 25 (600) 21 (1200) ###	65%, as glucuronide metabolites	Very small amounts	35%, as glucuronide metabolites	Very small amounts
Phenylbutazone	Slow, via hepatic microsomal enzymes		54–99 (average 77) 105 ****	61–75; may remain in body 7–10 days after last dose	Trace amounts	25–27	<5
Oxyphenbutazone (active metabolite)				4
Piroxicam	Hepatic		50 ††††	66	<5	33
Sulindac	Hepatic; sulfide metabolite, not sulindac itself, is active		7.8	50		‡‡
Sulindac sulfide			16.4	<1		25 ‡‡
Tenoxicam			72±28 (range, 32–110)	66	<0.5	17
Tiaprofenic Acid			Tablets 1.7; 2.5 **** Extended-release Capsules (at steady-state) 4.2	60	90	40
Tolmetin	Hepatic	1–2	5	100 in 24 hr	Up to 17

^* Dialyzable.
^† Some metabolites may be active.
^‡ Not dialyzable.
^§ In patients with renal function impairment. GFR=glomerular filtration rate in mL per minute, when specified.
^# Reason for prolonged half-life is unclear because only small amounts are excreted unchanged. It has been proposed that biliary excretion of metabolites with subsequent hydrolysis to, and reabsorption of, the parent compound may occur in renal failure. Alternatively, slower renal excretion may permit hydrolysis of an unstable metabolite to the parent compound.
^** Excretion (renal plus biliary/fecal) complete within 24 hours.
^††  Subject to large interindividual variation, possibly because of differences in enterohepatic circulation and subsequent reabsorption.
^‡‡ Undergoes extensive enterohepatic circulation.
^§§ Acyl-glucuronide conjugate is unstable; in patients with renal function impairment, this conjugate may accumulate and be deconjugated to the parent compound.
^## Higher values for the extended-release dosage forms reflect prolonged absorption. In geriatric patients, values for the capsules and the extended-release capsules are prolonged by 26% and 54%, respectively. Also, values for the capsules may be prolonged to 3 hours in patients with mild renal function impairment and to 5 to 9 hours in patients with moderate to severe renal function impairment.
^*** Enterohepatic recirculation has been proposed to account for elimination of the other 40% of the dose; however, studies to confirm this possibility have not been done.
^††† Hydroxymethyl metabolite has anti-inflammatory activity approximately 20% of that of the parent compound.
^‡‡‡ In geriatric patients, in whom values are especially subject to substantial interpatient variability; values as high as 74 hours have been measured. Also, increased to about 39 hours in patients with creatinine clearances <30 mL/minute/1.73 cubic meters of body surface area, but not in patients with lesser degrees of renal function impairment or in patients receiving hemodialysis.
^§§§ In patients with moderately severe renal function impairment (creatinine clearances 10–30 mL/min/1.73 cubic meters of body surface area).
^### Several studies reported terminal elimination half-life values of 50 to 60 hours. However, these lower ``accumulation"" half-life values are recommended for use in clinical practice, e.g., for estimating time to reach steady-state, determining appropriate dosing intervals, and determining intervals for dosage adjustment.
^**** In geriatric patients.
^††††  Average; usual range 30 to 60 hours, but values ranging from 14 to 158 hours have been reported. Half-life may be especially prolonged in patients with renal function impairment.

Physicochemical characteristics:

Chemical group—
    Fenamate derivatives: Meclofenamate, mefenamic acid.
    Indoleacetic acid derivative: Indomethacin. Indomethacin is chemically related to the pyrroleacetic acid derivatives sulindac and tolmetin and to the pyranoindoleacetic acid derivative etodolac.
    Naphthylalkanone derivative: Nabumetone. ^{211}
    Oxicam derivative: Meloxicam, piroxicam, tenoxicam.
    Phenylacetic acid derivative: Diclofenac.
    Propionic acid derivatives: Fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, tiaprofenic acid.
    Pyranoindoleacetic acid: Etodolac. ^{244} This medication is chemically related to the indoleacetic acid derivative indomethacin and to the pyrroleacetic acid derivatives sulindac and tolmetin.
    Pyrazole derivative: Phenylbutazone.
    Pyrroleacetic acid derivatives: Sulindac, tolmetin. These medications are chemically related to the indoleacetic acid derivative indomethacin and to the pyranoindoleacetic acid derivative etodolac.
    Salicylic acid derivative: Diflunisal. However, diflunisal is not metabolized to salicylic acid in vivo
Molecular weight—
^{245}    Diclofenac potassium: 334.24
    Diclofenac sodium: 318.13
    Diflunisal: 250.2
    Etodolac: 287.36
    Fenoprofen calcium: 558.64
    Floctafenine: 406.36
    Flurbiprofen: 244.26
    Ibuprofen: 206.28
    Indomethacin: 357.79
    Ketoprofen: 254.28
    Meclofenamate sodium: 336.15
    Mefenamic acid: 241.29
    Meloxicam: 351.4
    Nabumetone: 228.29


Active nabumetone metabolite 6-methoxy-2-naphthylacetic acid (6-MNA)—216.25 ^{246}
    Naproxen: 230.26
    Naproxen sodium: 252.24
    Oxaprozin: 293.32
    Phenylbutazone: 308.38
    Piroxicam: 331.35
    Sulindac: 356.41
    Tenoxicam: 337.37
    Tiaprofenic acid: 260.31
    Tolmetin sodium: 315.3


Other characteristics
    Ketoprofen: Highly lipophilic.
    Oxaprozin: Lipophilic.

pKa—
    Diclofenac potassium: 4.0 ^{158}
    Diclofenac sodium: 4.0 ^{158}
    Diflunisal: 3.3 ^{05}
    Etodolac: 4.65 ^{177}
    Fenoprofen calcium: 4.5 (25 °C) ^{03}
    Flurbiprofen: 4.22 ^{247}
    Ibuprofen: 4.43 ^{247}
    Indomethacin: 4.5 ^{32}
    Ketoprofen: 5.94 (in methanol:water [3:1]) ^{205}
    Mefenamic acid: 4.2 ^{06}
    Meloxicam: 1.1 and 4.2 ^{320}
    Naproxen: 4.2 ^{07}
    Oxaprozin: 4.3 ^{163}
    Piroxicam: 1.8 and 5.1 ^{08}
    Tiaprofenic acid: 3.0 ^{48}
    Tolmetin sodium: 3.5 ^{09}

Note: 6-MNA, the active metabolite of nabumetone, but not nabumetone itself, is acidic. Other NSAIDs not listed above are also acidic.


Mechanism of action/Effect:

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the activity of the enzyme cyclo-oxygenase, resulting in decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid. Also, meclofenamate and mefenamic acid have been shown to inhibit competitively the actions of prostaglandins. Although the resultant decrease in prostaglandin synthesis and activity in various tissues may be responsible for many of the therapeutic (and adverse) effects of NSAIDs, other actions may also contribute significantly to the therapeutic effects of these medications.


Antirheumatic (nonsteroidal anti-inflammatory):

Act via analgesic and anti-inflammatory mechanisms; the therapeutic effects are not due to pituitary-adrenal stimulation. These medications do not affect the progressive course of rheumatoid arthritis.



Analgesic:

May block pain impulse generation via a peripheral action that may involve reduction of the activity of prostaglandins, and possibly inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation. The antibradykinin activity of ketoprofen may also be involved in relief of pain, because bradykinin has been shown to act together with prostaglandins to cause pain. ^{248}



Antigout agent:

Act via analgesic and anti-inflammatory mechanisms; do not correct hyperuricemia.



Anti-inflammatory (nonsteroidal):

Exact mechanisms have not been determined. NSAIDs may act peripherally in inflamed tissue, probably by reducing prostaglandin activity in these tissues and possibly by inhibiting the synthesis and/or actions of other local mediators of the inflammatory response. Inhibition of leukocyte migration, inhibition of the release and/or actions of lysosomal enzymes, and actions on other cellular and immunological processes in mesenchymal and connective tissue may be involved. Indomethacin has been shown to inhibit phosphodiesterase, with a resultant increase in intracellular cyclic adenosine monophosphate (cAMP) concentration. Ketoprofen has been shown to inhibit leukotriene synthesis, inhibit bradykinin activity, and stabilize lysosomal membranes. ^{35}



Antipyretic:

Probably produce antipyresis by acting centrally on the hypothalamic heat-regulating center to produce peripheral vasodilation, resulting in increased blood flow through the skin, sweating, and heat loss. The central action probably involves reduction of prostaglandin activity in the hypothalamus.



Antidysmenorrheal:

By inhibiting the synthesis and activity of intrauterine prostaglandins (which are thought to be responsible for the pain and other symptoms of primary dysmenorrhea), NSAIDs decrease uterine contractility ^{07} and uterine pressure, ^{31} increase uterine perfusion, and relieve ischemic as well as spasmodic pain. ^{07} The antibradykinin activity of ketoprofen may also be involved in relief of dysmenorrhea, because bradykinin has been shown to induce uterine contractions and to act together with prostaglandins to cause pain. ^{248} Also, NSAIDs may relieve to some extent extrauterine symptoms (such as headache, nausea, and vomiting) that may be associated with excessive prostaglandin production. ^{07}



Vascular headache prophylactic and suppressant:

Analgesic actions may be involved in relief of headache. Also, by reducing prostaglandin activity, NSAIDs may directly prevent or relieve certain types of headache thought to be caused by prostaglandin-induced dilation or constriction of cerebral blood vessels.



Prostaglandin synthesis inhibitor, renal:

Inhibition of renal prostaglandin synthesis probably is responsible for indomethacin"s beneficial effect in patients with Bartter"s syndrome, which is thought to be caused by excessive production of renal prostaglandins.



Other actions/effects:

Most of the NSAIDs inhibit platelet aggregation. However, their antiplatelet effect, unlike that of aspirin, is reversible. ^{249} Single doses of 4 to 10 mg of flurbiprofen inhibit platelet aggregation. ^{{29} {51} {61}} Oxaprozin is as potent as aspirin in inhibiting platelet aggregation induced by epinephrine or collagen in vitro . ^{{255} {256} {257}} With diflunisal, the effect is clinically significant only with greater-than-recommended daily doses. ^{24} Also, usual doses of ^{55} diclofenac, ^{{158} {218}} meclofenamate, ^{37} mefenamic acid, ^{38} or nabumetone (as determined after administration of 1000 mg per day for 7 to 10 days) ^{{210} {250} {251} {252}} may not significantly alter platelet aggregability. Recovery of platelet function may occur within 1 day after discontinuation of diclofenac, ^{{13} {57}} diflunisal, ^{13} flurbiprofen, ^{{51} {61}} ibuprofen, indomethacin, or sulindac; 2 days after discontinuation of tolmetin; 4 days after discontinuation of naproxen; or 2 weeks following discontinuation of slowly eliminated agents such as oxaprozin ^{257} or piroxicam.

Diclofenac, ^{51} diflunisal, etodolac, ^{177} oxaprozin, ^{{253} {254}} and phenylbutazone ^{224} also have uricosuric activity.

Phenylbutazone also induces hepatic microsomal enzyme activity.

Studies have demonstrated that IgM rheumatoid factor production (which may be partially mediated by prostaglandins) may be decreased (but not totally inhibited) during NSAID therapy. ^{{10} {11} {12}} However, because these medications do not affect the progressive course of rheumatoid arthritis, the clinical significance of this effect has not been determined. ^{236}

It has been proposed that the gastrointestinal toxicity of NSAIDs may be caused primarily by reduction of the synthesis and activity of prostaglandins (which exert a protective effect on the gastrointestinal mucosa) because upper gastrointestinal toxicity has been reported following rectal or parenteral administration of some of these medications. However, when administered orally, some of these acidic medications probably also exert a direct irritant or erosive effect on the mucosa. ^{14} Because nabumetone is a nonacidic prodrug, ^{{210} {259}} and the active metabolite 6-MNA is not formed until after absorption, ^{{210} {250} {259}} the risk of serious upper gastrointestinal tract toxicity may be lower with nabumetone than with other NSAIDs. ^{{250} {260}} Also, in one study, gastric and duodenal prostaglandin concentrations were not altered by 4 weeks of administration of therapeutic doses of etodolac. ^{261}

The renal toxicity associated with NSAIDs (i.e., decreased renal perfusion, sodium and fluid retention, and decreased renal function) may be caused by inhibition of renal prostaglandins, which are directly involved in the maintenance of renal hemodynamics and sodium and fluid balance. Renal prostaglandins are especially important in maintaining renal function in the presence of generalized vasoconstriction or volume depletion. ^{{14} {253} {258}} Sulindac is a prodrug; its sulfide metabolite is the active substance. Because this active metabolite is not excreted via the kidneys, renal toxicity may be less likely with sulindac than with other NSAIDs. However, there have been reports of renal toxicity associated with sulindac therapy. ^{223} Etodolac has been shown to decrease some measures of renal function, ^{{262} {263}} with maximum effects occurring within 1.5 ^{{262} {263}} to 2.5 ^{263} hours after a dose. However, with administration of up to 500 mg every 12 hours, recovery of renal function occurred prior to administration of the next dose, even in patients with pre-existing mild to moderate renal function impairment (creatinine clearances ranging from 20 to 88 mL per minute). ^{{262} {263}} Whether more frequent administration of etodolac may cause cumulative effects on renal function has not been determined. ^{264}

The analgesic, antipyretic, and anti-inflammatory effects of NSAIDs may mask symptoms of the onset and/or progression of an infection. ^{236}

Therapeutic effect

When these medications are used in the treatment of arthritis, their analgesic actions may produce some relief of pain within the first day or two. Significant relief of other symptoms of inflammation usually occurs within a few days to a week; however, in severe cases, 2 weeks or more of continuous use may be required. ^{236}

Drug and Indication	Onset of Action	Peak Effect	Duration of Action
Diclofenac {158}
Tablets
Pain	30 min		Up to 8 hr
Diflunisal
Pain	1 hr	2–3 hr	8–12 hr
Etodolac
Pain	30 min	1–2 hr
200 mg			4–5 hr
400 mg			5–6 hr, but 8–12 hr in some patients
Ibuprofen
Fever {139} {183}		2-4 hr
5 mg/kg			6 hr
10 mg/kg			8 hr or more
Pain	0.5 hr		4–6 hr
Indomethacin
Gout	2–4 hr
Heat, tender- ness		2–3 days
Swelling		3–5 days
Meclofenamate {178}
Pain	1 hr		4–6 hr
Naproxen {188}
Gout		1–2 days
Pain	1 hr	2–4 hr	Up to 7 hr
Piroxicam {122}
Gout	2–4 hr	3–5 days	24 hr

Synovial fluid concentrations

Studies with several of the NSAIDs have shown that these medications enter the synovial fluid and that, several hours after administration of a single dose, synovial fluid concentrations equal or exceed the simultaneously measured plasma concentration. ^{{23} {35} {48} {51} {61} {68} {69} {70} {77} {93} {291}} In addition, there is some evidence that ketoprofen, oxaprozin, ^{291} and possibly other NSAIDs, may accumulate in synovial fluid when administered chronically.

Drug and Dose	Concentration		Half-life * (hr)
	Time to Peak (hr)	Peak (mcg/mL)
Diclofenac	3 †	0.28 †	Up to 6
Etodolac ‡ {265}	2.7–3.7	Total 2.6 Free (unbound) 44–84 nanograms/mL	6.5–7
Flurbiprofen
100 mg †	5.2	4.4	4.6
Indomethacin
50 mg	2	0.69
Ketoprofen
50 mg	2	0.7–0.9
100 mg		0.7–0.9
Nabumetone {266}
1000 mg	±8	20 §; 35 #
Tenoxicam {180}
40 mg	10	1.82
Tiaprofenic Acid
Tablets
200 mg †	4