PIROXICAM
DESCRIPTION:
PIRICAM (piroxicam) is 4-Hydroxy-2-methyl-N-2- pyridinyl-2H-1.2-
benzothiazine-3- carboxamide 1.1-dioxide, an oxicam. Members of the oxicam
family are not carboxylic acids, but they are acidic by virtue of the enolic 4-
hydroxy substituent. PIRICAM occurs as a white crystalline solid, sparingly
soluble in water, dilute acid and most organic solvents. It is slightly soluble
in alcohols and in aqueous alkaline solution. It exhibits a weakly acidic 4-
hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8).
Molecular Formula: C15H13N3O4S
Molecular Weight 331.35
ACTIONS/CLINICAL PHARMACOLOGY:
PIRICAM has shown anti-inflammatory, analgesic and antipyretic properties in
animals. Edema, erythema, tissue proliferation, fever, and pain can all be
inhibited in laboratory animals by the administration of PIRICAM. It is
effective regardless of the etiology of the inflammation. The mode of action of
PIRICAM is not fully established at this time. However, a common mechanism for
the above effects may exist in the ability of PIRICAM to inhibit the
biosynthesis of prostaglandins, known mediators of inflammation.
It is established that PIRICAM does not act by stimulating the pituitary-adrenal
axis.
PIRICAM is well absorbed following oral administration. Drug plasma
concentrations are proportional for 10 and 20 mg doses, generally peak within
three to five hours after medication, and subsequently decline with a mean half-
life of 50 hours (range of 30 to 86 hours, although values outside of this range
have been encountered).
This prolonged half-life results in the maintenance of relatively stable plasma
concentrations throughout the day on once daily doses and to significant drug
accumulation upon multiple dosing. A single 20 mg dose generally produces peak
piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum drug plasma
concentrations, after repeated daily ingestion of 20 mg PIRICAM, usually
stabilize at 3-8 mcg/mL. 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.
PIRICAM and its biotransformation products are excreted in urine and feces, with
about twice as much appearing in the urine as the feces. Metabolism 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. Less than 5% of the daily dose is excreted unchanged.
Concurrent administration of aspirin (3900 mg/day) and PIRICAM (20 mg/day),
resulted in a reduction of plasma levels of piroxicam to about 80% of their
normal values. The use of PIRICAM in conjunction with aspirin is not recommended
because data are inadequate to demonstrate that the combination produces greater
improvement than that achieved with aspirin alone and the potential for adverse
reactions is increased. Concomitant administration of antacids had no effect on
PIRICAM plasma levels. The effects of impaired renal function or hepatic disease
on plasma levels have not been established.
PIRICAM, like salicylates and other nonsteroidal anti-inflammatory agents, is
associated with symptoms of gastrointestinal tract irritation (see ADVERSE
REACTIONS). However, in a study utilizing 51Cr-tagged red blood cells, 20 mg of
PIRICAM administered as a single dose for four days did not result in a
significant increase in fecal blood loss and did not detectably affect the
gastric mucosa. In the same study a total daily dose of 3900 mg of aspirin,
i.e., 972 mg q.i.d., caused a significant increase in fecal blood loss and
mucosal lesions as demonstrated by gastroscopy.
In controlled clinical trials, the effectiveness of PIRICAM (piroxicam) has been
established for both acute exacerbations and long-term management of rheumatoid
arthritis and osteoarthritis.
The therapeutic effects of PIRICAM are evident early in the treatment of both
diseases with a progressive increase in response over several (8-12) weeks.
Efficacy is seen in terms of pain relief and, when present, subsidence of
inflammation.
Doses of 20 mg/day PIRICAM display a therapeutic effect comparable to
therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal
effects and tinnitus.
PIRICAM 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.
INDICATIONS AND USAGE:
PIRICAM is indicated for acute or long-term use in the relief of signs and
symptoms of the following:
1. osteoarthritis
2. rheumatoid arthritis
Dosage recommendations for use in children have not been established.
CONTRAINDICATIONS:
PIRICAM should not be used in patients who have previously exhibited
hypersensitivity to it, or in individuals with the syndrome comprised of
bronchospasm, nasal polyps, and angioedema precipitated by aspirin or other
nonsteroidal anti-inflammatory drugs.
WARNINGS:
RISK OF GI ULCERATION, BLEEDING AND PERFORATION WITH NSAID THERAPY
Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation
can occur at any time, with or without warning symptoms, in patients treated
chronically with NSAID therapy. Although minor upper gastrointestinal problems,
such as dyspepsia, are common, usually developing early in therapy, physicians
should remain alert for ulceration and bleeding in patients treated chronically
with NSAIDs even in the absence of previous GI tract symptoms. In patients
observed in clinical trials of several months to two years duration, symptomatic
upper GI ulcers, gross bleeding or perforation appear to occur in approximately
1% of patients treated for 3-6 months, and in about 2-4% of patients treated for
one year. Physicians should inform patients about the signs and/or symptoms of
serious GI toxicity and what steps to take if they occur.
Studies to date have not identified any subset of patients not at risk of
developing peptic ulceration and bleeding. Except for a prior history of serious
GI events and other risk factors known to be associated with peptic ulcer
disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex)
have been associated with increased risk. Elderly or debilitated patients seem
to tolerate ulceration or bleeding less well than other individuals and most
spontaneous reports of fatal GI events are in this population. Studies to date
are inconclusive concerning the relative risk of various NSAIDs in causing such
reactions. High doses of any NSAID probably carry a greater risk of these
reactions, although controlled clinical trials showing this do not exist in most
cases. In considering the use of relatively large doses (within the recommended
dosage range), sufficient benefit should be anticipated to offset the potential
increased risk of GI toxicity.
PRECAUTIONS:
Renal Effects: As with other nonsteroidal anti- inflammatory drugs, long-term
administration of piroxicam to animals has resulted in renal papillary necrosis
and other abnormal renal pathology. In humans, there have been reports of acute
interstitial nephritis with hematuria, proteinuria, and occasionally, nephrotic
syndrome.
A second form of renal toxicity has been seen in patients with prerenal
conditions leading to a reduction in renal blood flow or blood volume, where the
renal prostaglandins have a supportive role in the maintenance of renal
perfusion. In these patients administration of an NSAID may cause a dose-
dependent reduction in prostaglandin formation and 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, and the elderly. Discontinuation of NSAID therapy is typically
followed by recovery to the pretreatment state.
Because of extensive renal excretion of piroxicam and its biotransformation
products (less than 5% of the daily dose excreted unchanged, see
ACTIONS/CLINICAL PHARMACOLOGY), lower doses of piroxicam should be anticipated
in patients with impaired renal function, and they should be carefully
monitored.
Although other nonsteroidal anti-inflammatory drugs do not have the same direct
effects on platelets that aspirin does, all drugs inhibiting prostaglandin
biosynthesis do interfere with platelet function to some degree; therefore,
patients who may be adversely affected by such an action should be carefully
observed when PIRICAM is administered.
Because of reports of adverse eye findings with nonsteroidal anti-inflammatory
agents, it is recommended that patients who develop visual complaints during
treatment with PIRICAM have ophthalmic evaluation.
As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one
or more liver tests may occur in up to 15% of patients. These abnormalities may
progress, may remain essentially unchanged, or may be transient with continued
therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver
dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT
or SGOT (AST) occurred in controlled clinical trials in less than 1% of
patients. 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 more severe hepatic reaction while on therapy with PIRICAM.
Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have
been reported with PIRICAM. Although such reactions are rare, if abnormal liver
tests persist or worsen, if clinical signs and symptoms consistent with liver
disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash,
etc.), PIRICAM should be discontinued. (See also ADVERSE REACTIONS.)
Although at the recommended dose of 20 mg/day of PIRICAM increased fecal blood
loss due to gastrointestinal irritation did not occur (see ACTIONS/CLINICAL
PHARMACOLOGY), in about 4% of the patients treated with PIRICAM alone or
concomitantly with aspirin, reductions in hemoglobin and hematocrit values were
observed. Therefore, these values should be determined if signs or symptoms of
anemia occur.
Peripheral edema has been observed in approximately 2% of the patients treated
with PIRICAM. Therefore, as with other nonsteroidal anti-inflammatory drugs,
PIRICAM should be used with caution in patients with heart failure, hypertension
or other conditions predisposing to fluid retention, since its usage may be
associated with a worsening of these conditions.
A combination of dermatological and/or allergic signs and symptoms suggestive of
serum sickness have occasionally occurred in conjunction with the use of
PIRICAM. These include arthralgias, pruritus, fever, fatigue, and rash including
vesiculo bullous reactions and exfoliative dermatitis.
INFORMATION FOR PATIENTS
PIRICAM, like other drugs of its class, is not free of side effects. The side
effects of these drugs can cause discomfort and, rarely, there are more serious
side effects, such as gastrointestinal bleeding, which may result in
hospitalization and even fatal outcomes.
NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) are often essential agents in the
management of arthritis, but they also may be commonly employed for conditions
which are less serious.
Physicians may wish to discuss with their patients the potential risks (see
WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections) and likely benefits of
NSAID treatment, particularly when the drugs are used for less serious
conditions where treatment without NSAIDs may represent an acceptable
alternative to both the patient and physician.
LABORATORY TESTS
Because serious GI tract ulceration and bleeding can occur without warning
symptoms, physicians should follow chronically treated patients for the signs
and symptoms of ulceration and bleeding and should inform them of the importance
of this follow-up (see Risk of GI Ulceration, Bleeding and Perforation with
NSAID Therapy).
DRUG INTERACTIONS
PIRICAM is highly protein bound, and, therefore, might be expected to displace
other protein-bound drugs. Although this has not occurred in In Vitro studies
with coumarin-type anticoagulants, interactions with coumarin-type
anticoagulants have been reported with PIRICAM since marketing, therefore,
physicians should closely monitor patients for a change in dosage requirements
when administering PIRICAM to patients on coumarin- type anticoagulants and
other highly protein- bound drugs.
Plasma levels of piroxicam are depressed to approximately 80% of their normal
values when PIRICAM is administered in conjunction with aspirin (3900 mg/day),
but concomitant administration of antacids has no effect on piroxicam plasma
levels (see ACTIONS/CLINICAL PHARMACOLOGY).
Nonsteroidal anti-inflammatory agents, including PIRICAM, have been reported to
increase steady state plasma lithium levels. It is recommended that plasma
lithium levels be monitored when initiating, adjusting and discontinuing
PIRICAM.
CARCINOGENESIS, CHRONIC ANIMAL TOXICITY AND IMPAIRMENT OF FERTILITY
Subacute and chronic toxicity studies have been carried out in rats, mice, dogs,
and monkeys.
The pathology most often seen was that characteristically associated with the
animal toxicology of anti-inflammatory agents: renal papillary necrosis (see
PRECAUTIONS) and gastrointestinal lesions.
In classical studies in laboratory animals piroxicam did not show any
teratogenic potential.
Reproductive studies revealed no impairment of fertility in animals.
PREGNANCY AND NURSING MOTHERS
Like other drugs which inhibit the synthesis and release of prostaglandins,
piroxicam increased the incidence of dystocia and delayed parturition in
pregnant animals when piroxicam administration was continued late into
pregnancy. Gastrointestinal tract toxicity was increased in pregnant females in
the last trimester of pregnancy compared to non-pregnant females or females in
earlier trimesters of pregnancy.
PIRICAM is not recommended for use in nursing mothers or in pregnant women
because of the animal findings and since safety for such use has not been
established in humans.
USE IN CHILDREN
Dosage recommendations and indications for use in children have not been
established.
DRUG INTERACTIONS:
PIRICAM is highly protein bound, and, therefore, might be expected to displace
other protein-bound drugs. Although this has not occurred in In Vitro studies
with coumarin-type anticoagulants, interactions with coumarin-type
anticoagulants have been reported with PIRICAM since marketing, therefore,
physicians should closely monitor patients for a change in dosage requirements
when administering PIRICAM to patients on coumarin- type anticoagulants and
other highly protein- bound drugs.
Plasma levels of piroxicam are depressed to approximately 80% of their normal
values when PIRICAM is administered in conjunction with aspirin (3900 mg/day),
but concomitant administration of antacids has no effect on piroxicam plasma
levels (see ACTIONS/CLINICAL PHARMACOLOGY).
Nonsteroidal anti-inflammatory agents, including PIRICAM, have been reported to
increase steady state plasma lithium levels. It is recommended that plasma
lithium levels be monitored when initiating, adjusting and discontinuing
PIRICAM.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The incidence of adverse reactions to piroxicam is based on clinical trials
involving approximately 2300 patients, about 400 of whom were treated for more
than one year and 170 for more than two years. About 30% of all patients
receiving daily doses of 20 mg of PIRICAM experienced side effects.
Gastrointestinal symptoms were the most prominent side effects- -occurring in
approximately 20% of the patients, which in most instances did not interfere
with the course of therapy. Of the patients experiencing gastrointestinal side
effects, approximately 5% discontinued therapy with an overall incidence of
peptic ulceration of about 1%.
Other than the gastrointestinal symptoms, edema, dizziness, headache, changes in
hematological parameters, and rash have been reported in a small percentage of
patients. Routine ophthalmoscopy and slit-lamp examinations have revealed no
evidence of ocular changes in 205 patients followed from 3 to 24 months while on
therapy.
INCIDENCE GREATER THAN 1% The following adverse reactions occurred more
frequently than 1 in 100.
Gastrointestinal: stomatitis, anorexia, epigastric distress*, nausea*,
constipation, abdominal discomfort, flatulence, diarrhea, abdominal pain,
indigestion
Hematological: decreases in hemoglobin* and hematocrit* (see PRECAUTIONS),
anemia, leucopenia, eosinophilia
Dermatologic: pruritus, rash
Central Nervous System: dizziness, somnolence, vertigo
Urogenital: BUN and creatinine elevations (see PRECAUTIONS)
Body As A Whole: headache, malaise
Special Senses: tinnitus
Cardiovascular/Respiratory: edema (see PRECAUTIONS)
*Reactions occurring in 3% to 9% of patients treated with PIRICAM. Reactions
occurring in 1-3% of patients are unmarked.
INCIDENCE LESS THAN 1% (Causal Relationship Probable)
The following adverse reactions occurred less frequently than 1 in 100. The
probability exists that there is a causal relationship between PIRICAM and these
reactions.
Gastrointestinal: liver function abnormalities, jaundice, hepatitis (see
PRECAUTIONS), vomiting, hematemesis, melena, gastrointestinal bleeding,
perforation and ulceration (see WARNINGS), dry mouth
Hematological: thrombocytopenia, petechial rash, ecchymosis, bone marrow
depression including aplastic anemia, epistaxis
Dermatologic: sweating, erythema, bruising, desquamation, exfoliative
dermatitis, erythema multiforme, toxic epidermal necrolysis, Stevens- Johnson
syndrome, vesiculo bullous reaction, photoallergic skin reactions
Central Nervous System: depression, insomnia, nervousness
Urogenital: hematuria, proteinuria, interstitial nephritis, renal failure,
hyperkalemia, glomerulitis, papillary necrosis, nephrotic syndrome (see
PRECAUTIONS)
Body As A Whole: pain (colic), fever, flu-like syndrome (see PRECAUTIONS)
Special Senses: swollen eyes, blurred vision, eye irritations
Cardiovascular/Respiratory: hypertension, worsening of congestive heart failure
(see PRECAUTIONS), exacerbation of angina
Metabolic: hypoglycemia, hyperglycemia, weight increase, weight decrease
Hypersensitivity: anaphylaxis, bronchospasm, urticaria/ angioedema, vasculitis,
"serum sickness" (see PRECAUTIONS)
INCIDENCE LESS THAN 1% (Causal Relationship Unknown)
Other adverse reactions were reported with a frequency of less than 1 in 100,
but a causal relationship between PIRICAM and the reaction could not be
determined.
Gastrointestinal: pancreatitis
Dermatologic: onycholysis, loss of hair
Central Nervous System: akathisia, hallucinations, mood alterations, dream
abnormalities, mental confusion, paresthesias
Urogenital System: dysuria
Body As A Whole: weakness
Cardiovascular/Respiratory: palpitations, dyspnea
Hypersensitivity: positive ANA
Special Senses: transient hearing loss
Hematological: hemolytic anemia
OVERDOSAGE:
In the event treatment for overdosage is required the long plasma half-life (see
ACTIONS/CLINICAL PHARMACOLOGY) of piroxicam should be considered. The absence of
experience with acute overdosage precludes characterization of sequelae and
recommendation of specific antidotal efficacy at this time. It is reasonable to
assume, however, that the standard measures of gastric evacuation and general
supportive therapy would apply. In addition to supportive measures, the use of
activated charcoal may effectively reduce the absorption and reabsorption of
piroxicam. Experiments in dogs have demonstrated that the use of multiple-dose
treatments with activated charcoal could reduce the half-life of piroxicam
elimination from 27 hours (without charcoal) to 11 hours and reduce the systemic
bioavailability of piroxicam by as much as 37% when activated charcoal is given
as late as 6 hours after administration of piroxicam.
DOSAGE AND ADMINISTRATION:
RHEUMATOID ARTHRITIS, OSTEOARTHRITIS
It is recommended that PIRICAM therapy be initiated and maintained at a single
daily dose of 20 mg. If desired the daily dose may be divided. Because of the
long half-life of PIRICAM, steady-state blood levels are not reached for 7-12
days. Therefore although the therapeutic effects of PIRICAM 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.
Dosage recommendations and indications for use in children have not been
established.
************************************************************************