(misoprostol, diclofenac sodium)

Prescribing Information
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12 CLINICAL PHARMACOLOGY

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ARTHROTEC is a combination product containing diclofenac sodium, an NSAID with analgesic, anti-inflammatory and antipyretic properties, and misoprostol, a GI mucosal protective prostaglandin-1 (PGE1) analog.

Diclofenac

The mechanism of action of diclofenac, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Diclofenac 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 diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Misoprostol

Misoprostol is a synthetic PGE1 analog with gastric antisecretory and mucosal protective properties. NSAIDs inhibit prostaglandin synthesis. A deficiency of prostaglandins within the gastric and duodenal mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by NSAIDs.

Misoprostol can increase bicarbonate and mucus production, but it has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to differentiate whether the ability of misoprostol to reduce the risk of gastric and duodenal ulcers is the result of its antisecretory effect, its mucosal protective effect, or both.

In vitro studies on canine parietal cells using titrated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereo-specific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained.

Misoprostol, over the range of 50 mcg to 200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter-lived, and only the 200 mcg dose had substantial effects on nocturnal secretion or on histamine- and meal-stimulated secretion.

Misoprostol also produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor intrinsic factor output.

12.3 Pharmacokinetics

General Pharmacokinetic Characteristics

The pharmacokinetic profiles of diclofenac and misoprostol administered as the fixed combination (ARTHROTEC 50 or 75) are similar to the profiles when the two drugs are administered as separate tablets (see Table 2). No pharmacokinetic interaction between the two drugs has been observed following multiple dosing. The diclofenac total exposure [area under the curve (AUC)] is dose-proportional within the range of 25 mg to 150 mg. Approximately dose-proportional increase in misoprostol exposure was also observed within the range of 200 mcg to 400 mcg. Neither diclofenac nor misoprostol accumulated in plasma following repeated doses of ARTHROTEC given every 12 hours under fasted conditions.

Table 2: Pharmacokinetic Parameters of Diclofenac and Misoprostol Acid Following Single Oral Doses of ARTHROTEC or Separate Products in Healthy Subjects
SD: Standard deviation of the mean; AUC: Area under the curve; Cmax: Peak concentration; Tmax: Time to peak concentration

MISOPROSTOL ACID Mean (SD)

Treatment (n=36)

Cmax (pg/mL)

Tmax (hr)

AUC(0–4h)
(pg∙hr/mL)

ARTHROTEC 50

441 (137)

0.30 (0.13)

266 (95)

Misoprostol

478 (201)

0.30 (0.10)

295 (143)

ARTHROTEC 75

304 (110)

0.26 (0.09)

177 (49)

Misoprostol

290 (130)

0.35 (0.12)

176 (58)

DICLOFENAC Mean (SD)

Treatment (n=36)

Cmax (ng/mL)

Tmax (hr)

AUC(0–12h)
(ng∙hr/mL)

ARTHROTEC 50

1207 (364)

2.4 (1.0)

1380 (272)

Diclofenac Sodium

1298 (441)

2.4 (1.0)

1357 (290)

ARTHROTEC 75

2025 (2005)

2.0 (1.4)

2773 (1347)

Diclofenac Sodium

2367 (1318)

1.9 (0.7)

2609 (1185)

Absorption

Diclofenac: Diclofenac is completely absorbed from the GI tract after oral administration under fasted condition, and peak plasma levels are achieved in 2 hours (range 1–4 hours), and the area under the plasma concentration curve (AUC) is dose-proportional within the range of 25 mg to 150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.5 and 2.0 mcg/mL for 50 mg and 75 mg doses, respectively. The diclofenac in ARTHROTEC is in a pharmaceutical formulation that resists dissolution in the low pH of gastric fluid but allows a rapid release of drug in the higher pH environment of the duodenum. Only 50% of the absorbed dose is systemically available due to first pass metabolism (i.e., oral bioavailability is 50%).

Misoprostol: Misoprostol is rapidly absorbed following oral administration of ARTHROTEC, and misoprostol acid (active metabolite) reaches a maximum plasma concentration in approximately 20 minutes. Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food, and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid; this effect does not appear to be clinically important.

Food decreases the multiple-dose bioavailability profile of ARTHROTEC 50 and ARTHROTEC 75.

Distribution

Diclofenac: The volume of distribution of diclofenac is approximately 0.55 L/kg. More than 99% of diclofenac is bound to plasma albumin.

Misoprostol: The plasma protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range.

After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/mL (CV 37%) and 20.9 pg/mL (CV 77%) after single 200 mcg and 600 mcg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to <1 pg/mL at 5 hours post-dose. These data may not reflect drug level in mature milk and in a daily dosing regimen for osteoarthritis or rheumatoid arthritis.

Elimination

Metabolism

Diclofenac: Metabolism is predominantly mediated via CYP2C9 in the liver. Five metabolites (4'hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac) have been identified. The major metabolite (4'-hydroxy-diclofenac) has very weak pharmacologic activity.

Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac.

Misoprostol: Undergoes rapid and extensive metabolism to its biologically active metabolite, misoprostol acid.

Excretion

Diclofenac: Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Approximately 65% of the dose is excreted in the urine and 35% in the bile. The elimination half-life of diclofenac is approximately 2 hours. The clearance of diclofenac is approximately 350 mL/min (equivalent to 21 L/h).

Conjugates of unchanged diclofenac account for 5% to 10% of the dose excreted in the urine and for less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted. Conjugates of the principal metabolite account for 20% to 30% of the dose excreted in the urine and for 10% to 20% of the dose excreted in the bile.

Conjugates of three other metabolites together account for 10% to 20% of the dose excreted in the urine and for small amounts excreted in the bile. The elimination half-life values for these metabolites are shorter than those for the parent drug. Urinary excretion of an additional metabolite (half-life = 80 hours) accounts for only 1.4% of the oral dose. The degree of accumulation of diclofenac metabolites is unknown. Some of the metabolites may have activity.

Misoprostol: After oral administration of radio-labeled misoprostol, approximately 70% of detected radioactivity appears in the urine. The elimination half-life is approximately 30 minutes.

Specific Populations

Geriatric Patients

No differences in the pharmacokinetics of diclofenac were observed in geriatric subjects (66 to 81 years; N=10) compared to younger adult subjects (26 to 46 years; N=10) following administration of diclofenac 50 mg twice daily for 4 weeks.

Though the mean AUC value of misoprostol acid for elderly subjects was 41% higher in geriatric healthy subjects (mean age, 69.5±4.6 years, N=24) compared to younger adult healthy subjects (mean age, 25.4±4.2 years, N=24) following single dose of misoprostol 400 µg, the increase in exposure is not clinically meaningful.

In a multiple-dose crossover study of ARTHROTEC administered twice daily to 24 subjects aged 65 years of age and older, misoprostol did not affect the pharmacokinetics of diclofenac [see Use in Specific Populations (8.5)].

Racial or Ethnic Groups

Pharmacokinetic differences due to race have not been identified.

Patients with Renal Impairment

In patients with renal impairment (N=5, creatinine clearance 3 to 42 mL/min) following intravenous administration of 50 mg diclofenac, AUC values and elimination rates were comparable to those in healthy subjects.

Pharmacokinetic studies with misoprostol in patients with severe renal impairment requiring hemodialysis (n=8, mean creatinine clearance 6.2±3.3 mL/min/1.73m2) who received a single dose of 400 mcg misoprostol during a interdialytic period showed an approximate doubling of elimination half-life, Cmax, and AUC of misoprostol acid compared to healthy subjects [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

In patients with biopsy-confirmed cirrhosis or chronic active hepatitis (variably elevated transaminases and mildly elevated bilirubin, N=10), diclofenac concentrations and urinary elimination values following administration of 100 mg oral solution were comparable to those in healthy subjects.

In a study of subjects with mild to moderate hepatic impairment, mean misoprostol acid AUC and Cmax showed approximately twice high as the mean values obtained in healthy subjects. Three subjects who had the lowest antipyrine and lowest indocyanine green clearance values had the highest misoprostol acid AUC and Cmax values.

Drug Interaction Studies

Diclofenac

Aspirin: When ARTHROTEC was administered with aspirin, the protein binding of diclofenac was reduced, although the clearance of the free diclofenac was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)].

Voriconazole: When a single dose diclofenac (50 mg) was coadministered with the last dose of voriconazole (400 mg every 12 hours on Day 1, followed by 200 mg every 12 hours on Day 2), the mean Cmax and AUC of diclofenac were increased by 114% and 78%, respectively, when compared to diclofenac alone [see Drug Interactions (7)].

In vitro, diclofenac interferes minimally with the protein binding of prednisolone (10% decrease in binding). Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalothin, erythromycin, and sulfamethoxazole have no influence, in vitro, on the protein binding of diclofenac in human serum.

Other drugs: In small groups of patients (7 to 10 patients/interaction study), the concomitant administration of azathioprine, gold, chloroquine, D-penicillamine, prednisolone, doxycycline or digitoxin did not significantly affect Cmax and AUC of diclofenac.

Misoprostol

Diazepam: Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart.

Other drugs: Pharmacokinetic studies also showed a lack of drug interaction with antipyrine or propranolol given with misoprostol.

Medication Guide

MEDICATION GUIDE

MEDICATION GUIDE
Medication Guide for
ARTHROTEC (ARTH' roe-tek)
(diclofenac sodium and misoprostol delayed- release tablets) for oral use

What is the most important information I should know about ARTHROTEC?
ARTHROTEC contains diclofenac (a nonsteroidal anti-inflammatory drug (NSAID)) and misoprostol, and can cause uterus to tear (uterine rupture), abortion, premature birth, or birth defects. The risk of uterine rupture increases as your pregnancy advances, if you have given birth to 5 or more children, and if you have had surgery on the uterus, such as a cesarean delivery.

Do not take ARTHROTEC if you are pregnant.

•
Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with ARTHROTEC. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with ARTHROTEC. Females who are able to become pregnant should use an effective form of birth control (contraception) during treatment with ARTHROTEC.

What is the most important information I should know about medicines containing Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?

NSAIDs can cause serious side effects, including:

•
Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase:
o
with increasing doses of NSAIDs
o
with longer use of NSAIDs

Do not take NSAID containing medicines right before or after a heart surgery called a "coronary artery bypass graft (CABG)."
Avoid taking NSAID containing medicines after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

•
Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:
o
anytime during use
o
without warning symptoms
o
that may cause death

The risk of getting an ulcer or bleeding increases with:

o
past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
o
taking medicines called "corticosteroids", "antiplatelet drugs", "anticoagulants", "SSRIs", or "SNRIs"
o
increasing doses of NSAIDs
o
longer use of NSAIDs
o
smoking
o
drinking alcohol
o
older age
o
poor health
o
advanced liver disease
o
bleeding problems

NSAID containing medicines should only be used:

o
exactly as prescribed
o
at the lowest dose possible for your treatment
o
for the shortest time needed

What is ARTHROTEC?
ARTHROTEC contains 2 medicines:

1.
Diclofenac is a non-steroidal anti-inflammatory drug (NSAID). See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?
2.
Misoprostol is a medicine used to protect the lining of the esophagus, stomach and intestines while taking diclofenac.

ARTHROTEC is a prescription medicine used to treat:

•
symptoms of osteoarthritis or rheumatoid arthritis in adults at high risk of developing stomach (gastric) and intestinal (duodenal) ulcers while taking NSAIDs.

It is not known if ARTHROTEC is safe and effective for use in children.

What are NSAIDs?
NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis.

Who should not take ARTHROTEC?
Do not take ARTHROTEC:

•
if you are pregnant.
•
right before or after heart bypass surgery.
•
if you currently have bleeding in your stomach (gastrointestinal bleeding).
•
if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
•
if you are allergic to diclofenac sodium and misoprostol, other prostaglandins or any other ingredients in ARTHROTEC. See the end of this Medication Guide for a list of ingredients in ARTHROTEC.

Before taking ARTHROTEC, tell your healthcare provider about all of your medical conditions, including if you:

•
have liver or kidney problems.
•
have high blood pressure.
•
have heart problems, including a history of heart failure or heart attack.
•
have asthma.
•
are pregnant or plan to become pregnant. See "Who should not take ARTHROTEC?"
•
are breastfeeding or plan to breast feed.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.

What are the possible side effects of NSAIDs?
NSAIDs can cause serious side effects, including:
See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?

•
new or worse high blood pressure
•
heart failure
•
liver problems including liver failure
•
kidney problems including kidney failure
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
asthma attacks in people who have asthma
•
Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness

Get emergency help right away if you get any of the following symptoms:

•
shortness of breath or trouble breathing
•
chest pain
•
weakness in one part or side of your body
•
slurred speech
•
swelling of the face or throat

Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:

•
nausea
•
more tired or weaker than usual
•
diarrhea
•
itching
•
your skin or eyes look yellow
•
indigestion or stomach pain
•
flu-like symptoms
•
vomit blood
•
there is blood in your bowel movement or it is black and sticky like tar
•
unusual weight gain
•
skin rash or blisters with fever
•
swelling of the arms, legs, hands and feet

If you take too much of your NSAID, call your healthcare provider or get medical help right away.
These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about NSAIDs

•
Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
•
Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

General information about the safe and effective use of NSAIDs
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.
If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

Active ingredients: diclofenac sodium, misoprostol.
Inactive ingredients: colloidal silicon dioxide, crospovidone, hydrogenated castor oil, hypromellose, lactose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, povidone (polyvidone) K-30, sodium hydroxide, starch (corn), talc, triethyl citrate.
This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.
For more information, go to www.pfizer.com or call 1-800-438-1985.
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LAB: 0793-9.0

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: November 2024

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