DRUGS & SUPPLEMENTS
RECENT MAJOR CHANGES
WARNING: RISK OF UTERINE RUPTURE, ABORTION, PREMATURE BIRTH, BIRTH
DEFECTS; AND SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
Arthrotec DELAYED-RELEASE TABLETS CONTAIN Arthrotec. ADMINISTRATION OF MISOPROSTOL TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, OR BIRTH DEFECTS. UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY. Arthrotec DELAYED-RELEASE TABLETS SHOULD NOT BE TAKEN BY PREGNANT WOMEN .
PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS. Arthrotec delayed-release tablets should not be used in women of childbearing potential unless the patient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and is at high risk of developing gastric or duodenal ulceration or for developing complications from gastric or duodenal ulcers associated with the use of the NSAID. In such patients, Arthrotec delayed-release tablets may be prescribed if the patient:
● has had a negative serum pregnancy test within 2 weeks prior to beginning therapy.
● is capable of complying with effective contraceptive measures.
● has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake.
● will begin Arthrotec delayed-release tablets only on the second or third day of the next normal menstrual period .
Cardiovascular Thrombotic Events
● Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use .
● Arthrotec is contraindicated in the setting of coronary artery bypass graft (CABG) surgery .
Gastrointestinal Bleeding, Ulceration, and Perforation
● NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events .
WARNING: RISK OF UTERINE RUPTURE, ABORTION, PREMATURE BIRTH, BIRTH DEFECTS; AND SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
See full prescribing information for complete boxed warning.
Arthrotec DELAYED-RELEASE TABLETS CONTAINS Arthrotec AND MISOPROSTOL. ADMINISTRATION OF MISOPROSTOL TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, OR BIRTH DEFECTS. UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY. Arthrotec DELAYED-RELEASE TABLETS SHOULD NOT BE TAKEN BY PREGNANT WOMEN ( 4 , 5.10 , 8.1 ).
PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS. Arthrotec delayed-release tablets should not be used in women of childbearing potential unless the patient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and is at high risk of developing gastric or duodenal ulceration or for developing complications from gastric or duodenal ulcers associated with the use of the NSAID. In such patients, d iclofenac sodium and misoprostol delayed-release tablets may be prescribed if the patient:
- has had a negative serum pregnancy test within 2 weeks prior to beginning therapy ( 8.3 ).
- is capable of complying with effective contraceptive measures.
- has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake.
- will begin Arthrotec delayed-release tablets only on the second or third day of the next normal menstrual period.
Cardiovascular Thrombotic Events Risk
- Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use ( 5.1 ).
- Di clofenac sodium and misoprostol is contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 ).
Gastrointestinal Bleeding, Ulceration, and Perforation Risk
- NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2 ).
1 INDICATIONS AND USAGE
Arthrotec delayed-release tablets are indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. For a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications [see Warnings and Precautions (5.2) ].
Arthrotec delayed-release tablets are a combination non-steroidal anti-inflammatory and prostaglandin E1 analog drug indicated for the treatment of signs and symptoms of osteoarthritis (OA) or rheumatoid arthritis (RA) in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications (1)
2 DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of Arthrotec delayed-release tablets and other treatment options before deciding to use Arthrotec delayed-release tablets. 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 Arthrotec delayed-release tablets, 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 given below.
Arthrotec delayed-release tablets are administered as Arthrotec delayed-release tablets (50 mg diclofenac sodium/0.2 mg misoprostol) or as Arthrotec delayed-release tablets (75 mg diclofenac sodium/0.2 mg misoprostol).
Note: See Special Dosing Considerations section below.
For osteoarthritis, the dosage for maximal GI mucosal protection is Arthrotec delayed-release tablets 50 mg/0.2 mg three times a day. For patients who experience intolerance, Arthrotec delayed-release tablets 75 mg/0.2 mg two times a day or Arthrotec delayed-release tablets 50 mg/0.2 mg two times a day can be used, but are less effective in preventing ulcers. This fixed combination product, Arthrotec delayed-release tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:
For rheumatoid arthritis, the dosage is Arthrotec delayed-release tablets 50 mg/0.2 mg three or four times a day. For patients who experience intolerance, Arthrotec delayed-release tablets 75 mg/0.2 mg two times a day or Arthrotec delayed-release tablets 50 mg/0.2 mg two times a day can be used, but are less effective in preventing ulcers. This fixed combination product, Arthrotec delayed-release tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:
Special Dosing Considerations :
Arthrotec delayed-release tablets contain misoprostol, which provides protection against gastric and duodenal ulcers [see Clinical Studies (14) ]. For gastric ulcer prevention, the 200 mcg four and three times a day regimens are therapeutically equivalent, but more protective than the two times a day regimen. For duodenal ulcer prevention, the four times a day regimen is more protective than the three or two times a day regimens. However, the four times a day regimen is less well tolerated than the three times a day regimen because of usually self-limited diarrhea related to the misoprostol dose [see Adverse Reactions (6.1) ], and the two times a day regimen may be better tolerated than three times a day in some patients.
Dosages may be individualized using the separate products (misoprostol and diclofenac), after which the patient may be changed to the appropriate dose of Arthrotec delayed-release tablets. If clinically indicated, misoprostol co-therapy with Arthrotec delayed-release tablets, or use of the individual components to optimize the misoprostol dose and/or frequency of administration, may be appropriate. The total dose of misoprostol should not exceed 800 mcg/day, and no more than 200 mcg of misoprostol should be administered at any one time. Doses of diclofenac higher than 150 mg/day in osteoarthritis or higher than 225 mg/day in rheumatoid arthritis are not recommended.
When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of Arthrotec delayed-release tablets 50 mg/0.2 mg two times a day.
For additional information, it may be helpful to refer to the package inserts for misoprostol and diclofenac.
3 DOSAGE FORMS AND STRENGTHS
Arthrotec delayed-release tablets, USP:
50 mg/0.2 mg tablet is white to off white, round, biconvex tablets, plain on one side and debossed with “0397” on the other side.
75 mg/0.2 mg tablet is white to off white, round, biconvex tablets, plain on one side and debossed with “0398” on the other side.
Arthrotec delayed-release tablets, USP 50 mg/0.2 mg and 75 mg/0.2 mg (3)
Arthrotec is contraindicated in the following patients:
● Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to Arthrotec, other prostaglandins, or any components of the drug product [see Warnings and Precautions ( 5.7 , 5.9 )]
● History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions ( 5.7 , 5.8 )]
● In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1) ]
● Pregnancy. Use of Arthrotec delayed-release tablets during pregnancy can result in maternal and fetal harm, including abortion, premature birth, birth defects, and uterine rupture [see Use in Specific Populations (8.1) ]
● Active gastrointestinal bleeding [see Warnings and Precautions (5.2) ]
5 WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2) ].
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4) ].
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of Arthrotec in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Arthrotec is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including diclofenac, cause serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
● Use the lowest effective dosage for the shortest possible duration.
● Avoid administration of more than one NSAID at a time.
● Avoid use in patients at high risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
● Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
● If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue Arthrotec until a serious GI adverse event is ruled out.
● In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7) ].
In clinical trials with Arthrotec, meaningful elevation of ALT (SGPT, more than 3 times the ULN [ULN = the upper limit of the normal range]) occurred in 1.6% of 2,184 patients treated with Arthrotec and misoprostol and in 1.4% of 1,691 patients treated with Arthrotec. These increases were generally transient, and enzyme levels returned to within the normal range upon discontinuation of therapy with Arthrotec delayed-release tablets. The misoprostol component of Arthrotec delayed-release tablets does not appear to exacerbate the hepatic effects caused by the Arthrotec component.
In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).
In a large, open-label, controlled trial of 3,700 patients treated with oral Arthrotec for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.
Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.
In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.
Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.
If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), Arthrotec delayed-release tablets should be discontinued immediately.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Arthrotec delayed-release tablets immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver related event in patients treated with Arthrotec, the lowest effective dose should be used for the shortest duration possible. Exercise caution when prescribing Arthrotec delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).
NSAIDs, including Arthrotec, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7) ].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
5.5 Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7) ].
Avoid the use of Arthrotec delayed-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Arthrotec delayed-release tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
5.6 Renal Toxicity and Hyperkalemia
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of Arthrotec and misoprostol in patients with advanced renal disease. The renal effects of Arthrotec and misoprostol may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating Arthrotec. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Arthrotec [see Drug Interactions ]. Avoid the use of Arthrotec in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Arthrotec delayed-release tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Increases in serum potassium concentration, including hyperkalemia, with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
5.7 Anaphylactic Reactions
Diclofenac/misoprostol has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac/misoprostol and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8) ].
Seek emergency help if an anaphylactic reaction occurs.
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Arthrotec is contraindicated in patients with this form of aspirin sensitivity [see Contraindications ]. When Arthrotec delayed-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
5.9 Serious Skin Reactions
NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Arthrotec delayed-release tablets at the first appearance of skin rash or any other sign of hypersensitivity. Arthrotec is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4) ].
5.10 Premature Closure of Fetal Ductus Arteriosus
Diclofenac may cause premature closure of the fetal ductus arteriosus. Arthrotec is contraindicated in pregnant women. Advise pregnant women of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiation of Arthrotec. Advise females of reproductive potential to use effective contraception during treatment with Arthrotec delayed-release tablets [see Contraindications and Use in Specific Populations ( 8.1 , 8.3 )].
5.11 Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Arthrotec has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including Arthrotec, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7) ].
5.12 Masking of Inflammation and Fever
The pharmacological activity of Arthrotec in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
5.13 Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions ( 5.2 , 5.6 )].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Most common adverse reactions (incidence greater than 2% from clinical trials) are: abdominal pain, diarrhea, dyspepsia, nausea, flatulence, gastritis, vomiting, constipation, headache, dizziness, alanine aminotransferase increased, hematocrit decreased (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience
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.
Adverse reaction information for Arthrotec is derived from Phase III multinational controlled clinical trials in over 2,000 patients receiving Arthrotec delayed-release tablets, 50 mg/0.2 mg or Arthrotec delayed-release tablets, 75 mg/0.2 mg, as well as from blinded, controlled trials of diclofenac delayed-release tablets and misoprostol tablets.
GI disorders had the highest reported incidence of adverse events for patients receiving diclofenac sodium and misoprostol. These events were generally minor, but led to discontinuation of therapy in 9% of patients on Arthrotec and 5% of patients on diclofenac. For GI ulcer rates, [see Clinical Studies (14) ].
Arthrotec can cause more abdominal pain, diarrhea, and other GI symptoms than diclofenac alone.
Diarrhea and abdominal pain developed early in the course of therapy, and were usually self-limited (resolved after 2 to 7 days). Rare instances of profound diarrhea leading to severe dehydration have been reported in patients receiving misoprostol. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if Arthrotec is prescribed. The incidence of diarrhea can be minimized by administering Arthrotec with food and by avoiding coadministration with magnesium-containing antacids.
Gynecological disorders previously reported with misoprostol use have also been reported for women receiving Arthrotec. Postmenopausal vaginal bleeding may be related to administration of Arthrotec. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology [see Boxed Warnings , Contraindications (4) and Warnings and Precautions (5) ].
Overall, there were no significant differences in the safety profile of Arthrotec in over 500 patients 65 years of age or older compared with younger patients.
Other adverse experiences reported occasionally with Arthrotec, diclofenac or other NSAIDs, or misoprostol are:
Body as a whole: asthenia, fatigue, malaise.
Central and peripheral nervous system: dizziness, drowsiness, headache, insomnia, paresthesia, vertigo.
Digestive: anorexia, appetite changes, constipation, dry mouth, dysphagia, esophageal ulceration, oesophagitis, eructation, gastritis, gastroesophageal reflux, GI neoplasm benign, peptic ulcer, tenesmus, vomiting.
Female reproductive disorders: breast pain, dysmenorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage.
Hemic and lymphatic system: epistaxis, leukopenia, melena, purpura, decreased hematocrit.
Metabolic and nutritional: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, dehydration, hyponatremia.
Musculoskeletal system: arthralgia, myalgia.
Psychiatric: anxiety, concentration impaired, depression, irritability.
Respiratory system: asthma, coughing, hyperventilation.
Skin and appendages: alopecia, eczema, pemphigoid reaction, photosensitivity, sweating increased, pruritus.
Special senses: taste perversion, tinnitus.
Renal and urinary disorders: dysuria, nocturia, polyuria, proteinuria, urinary tract infection.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval of diclofenac sodium and misoprostol, diclofenac or misoprostol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliable estimate their frequency or establish a causal relationship to drug exposure.
Body as a whole: death, fever, infection, sepsis, chills, edema.
Cardiovascular system: arrhythmia, atrial fibrillation, congestive heart failure, hypertension, hypotension, increased CPK, increased LDH, myocardial infarction, palpitations, phlebitis, premature ventricular contractions, syncope, tachycardia, vasculitis.
Central and peripheral nervous system: coma, convulsions, hyperesthesia, hypertonia, hypoesthesia, meningitis, migraine, neuralgia, somnolence, stroke, tremor.
Congenital, familial and genetic disorders: birth defects.
Digestive: enteritis, GI bleeding, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, stomatitis and ulcerative stomatitis.
Female reproductive disorders: intermenstrual bleeding, leukorrhea, vaginitis, uterine cramping, uterine hemorrhage.
Hemic and lymphatic system: agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, hemolytic anemia, leukocytosis, lymphadenopathy, pancytopenia, pulmonary embolism, rectal bleeding, thrombocythemia, thrombocytopenia.
Hypersensitivity: angioedema, laryngeal/pharyngeal edema, urticaria.
Liver and biliary system: abnormal hepatic function, bilirubinemia, liver failure, pancreatitis, hepatitis, jaundice.
Male reproductive disorders: impotence, perineal pain.
Metabolic and nutritional: BUN increased, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, periorbital edema, porphyria, weight changes, fluid retention.
Pregnancy, puerperium and perinatal conditions: abnormal uterine contractions, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death.
Psychiatric: confusion, disorientation, dream abnormalities, hallucinations, nervousness, paranoia, psychotic reaction.
Reproductive system and breast disorders: female fertility decreased.
Respiratory system: dyspnea, pneumonia, respiratory depression.
Skin and appendages: acne, bruising, erythema multiforme, exfoliative dermatitis, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous reactions (bullous eruption).
Special senses: hearing impairment, taste loss.
Renal and urinary disorders: cystitis, hematuria, interstitial nephritis, micturition frequency, nephrotic syndrome, oliguria, papillary necrosis, renal failure, glomerulonephritis membranous, glomerulonephritis minimal lesion, glomerulohephritis.
Vision: amblyopia, blurred vision, conjunctivitis, glaucoma, iritis, lacrimation abnormal, night blindness, vision abnormal.
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of Arthrotec and misoprostol in women who have difficulties conceiving
Arthrotec is contraindicated in pregnant women [see Contraindications (4) ]. There are no adequate and well-controlled studies of Arthrotec in pregnant women; however, there is information available about the active drug components of Arthrotec delayed-release tablets, misoprostol and Arthrotec. Administration of misoprostol to pregnant women can cause abortion, premature birth, or birth defects. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug’s teratogenic mechanism has not been demonstrated. Use of NSAIDS, including diclofenac, during the third trimester of pregnancy increases the risk of premature closure of fetal ductus arteriosus [see Data ]. There are clinical considerations when misoprostol and diclofenac are used in pregnant women [see Clinical Considerations ]. In reproduction studies with pregnant rabbits, there were no skeletal or visceral malformations when the combination of Arthrotec was administered during organogenesis at doses less than the maximum recommended human doses (MRHD); however, embryotoxicity was observed at this exposure [see Data ]. 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 diclofenac, resulted in increased pre- and post-implantation loss. If a woman becomes pregnant while taking Arthrotec, discontinue the drug and advise the woman of the potential risks to her and to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Maternal Adverse Reactions
Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication. A major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, severe bleeding, shock, and maternal death have been reported when misoprostol was administered to pregnant women to induce labor to induce abortion beyond the eight week of pregnancy. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. Arthrotec delayed-release tablets, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be incomplete.
Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy. Severe vaginal bleeding, retained placenta, shock, and pelvic pain have also been reported. These women were administered misoprostol vaginally and/or orally over a range of doses. If a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.
Arthrotec is contraindicated in pregnant women [see Contraindications (4) ].
Fetal/Neonatal Adverse Reactions
Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Use of misoprostol for the induction of labor in the third trimester was associated with uterine hyperstimulation with resulting changes in the fetal heart rate (fetal bradycardia) and fetal death. Arthrotec is contraindicated in pregnant women [see Contraindications (4) ].
Diclofenac may cause premature closure of the ductus arteriosus in a fetus [see Warnings and Precautions (5.10) ].
Labor or Delivery
There are no studies on the effects of Arthrotec or diclofenac during labor or delivery. In animal studies, NSAIDS, including diclofenac, are known to inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. In humans, some case reports and studies have associated misoprostol with risk of stillbirth, uterine hyperstimulation, perineal tear, amniotic fluid embolism, severe bleeding, shock, uterine rupture and death.
Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.
Data from observational studies regarding potential embryo-fetal risks of NSAID use (including diclofenac) in the first or second trimesters of pregnancy are inconclusive. However, use of NSAIDS (including diclofenac) during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus.
The reproductive and developmental effects of both the combination of Arthrotec and each component of Arthrotec delayed-release tablets alone have been studied in animals. In all studies there was no evidence of teratogenicity. In an oral teratology study in pregnant rabbits, Arthrotec was administered at dose combinations (diclofenac and misoprostol, 250:1 ratio) up to 10 mg/kg/day Arthrotec (120 mg/m2/day, 0.8 times the recommended maximum human dose based on body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m2/day, 0.8 times the recommended maximum human dose based on body surface area) and there was no evidence of teratogenicity. At the high dose, there was evidence of embryotoxicity (resorption and decreased fetal body weight) and maternal toxicity (decreased food intake and weight gain).
In oral teratology studies with misoprostol in pregnant rats at doses up to 1.6 mg/kg/day (9.6 mg/m2/day, 16 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 1.0 mg/kg/day (12 mg/m2/day, 20 times the recommended maximum human dose based on body surface area), there was no evidence of teratogenicity.
In oral teratology studies with Arthrotec in pregnant mice at doses up to 20 mg/kg/day (60 mg/m2/day, 0.4 times the recommended maximum human dose based on body surface area), pregnant rats at doses up to 10 mg/kg/day (60 mg/m2/day, 0.4 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 10 mg/kg/day (120 mg/m2/day, 0.8 times the recommended maximum human dose based on body surface area), there was no evidence of teratogenicity.
No lactation studies have been conducted with Arthrotec; however, limited published literature reports that diclofenac and the active metabolite of misoprostol are present in breast milk [see Clinical Pharmacology ]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Arthrotec and any potential adverse effects on the breastfed infant from the Arthrotec or from the underlying maternal condition.
8.3 Females and Males of Reproductive Potential
Verify pregnancy status for females of reproductive potential within 2 weeks prior to initiating Arthrotec.
Arthrotec can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with Arthrotec.
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Arthrotec, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1) ]. 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 Arthrotec, in women who have difficulties conceiving or who are undergoing investigation of infertility.
8.4 Pediatric Use
Safety and effectiveness of Arthrotec in pediatric patients have not been established.
8.5 Geriatric Use
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 ( 5.1 , 5.2 , 5.3 , 5.6 , 5.13 )].
Of the more than 2,100 subjects in clinical studies with Arthrotec, 25% were 65 and over, while 6% were 75 and over. In studies with diclofenac, 31% of subjects were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Diclofenac is known to be substantially excreted by the kidney, and the risk of toxic reactions to Arthrotec may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3) ].
Based on studies in the elderly, no adjustment of the dose of Arthrotec is necessary in the elderly for pharmacokinetic reasons [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6 , 5.13 ) and Clinical Pharmacology (12.3) ], although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging.
The toxic dose of Arthrotec has not been determined. However, signs of overdosage from the components of the product have been described.
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been 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 )].
Clinical signs that may suggest Arthrotec overdose include GI complaints, confusion, drowsiness, or general hypotonia.
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of GI discomfort being reported. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia.
Symptoms of overdosage with Arthrotec should be treated with supportive therapy. In case of acute overdosage, gastric lavage is recommended. Induced diuresis may be beneficial because Arthrotec metabolites are excreted in the urine. The effect of dialysis or hemoperfusion on the elimination of Arthrotec (99% protein bound) and misoprostol acid remains unproven. The use of oral activated charcoal may help to reduce the absorption of Arthrotec.
For additional information about overdosage treatment contact a poison control center (1-800-222-1222).
Arthrotec delayed-release tablets, USP are a combination product containing Arthrotec, a nonsteroidal anti-inflammatory drug (NSAID) with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin E1 analog. Arthrotec delayed-release tablets, USP are white to off-white, round, biconvex tablets, and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg or 75 mg Arthrotec surrounded by an outer mantle containing 0.2 mg misoprostol.
Arthrotec is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Arthrotec is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Arthrotec is sparingly soluble in water. Its chemical formula and name are:
C14H10Cl2NO2Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt.
Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are:
C22H38O5 [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate.
Inactive ingredients in Arthrotec delayed-release tablets include: colloidal silicon dioxide; crospovidone; hydrogenated castor oil; hypromellose; lactose; magnesium stearate; methacrylic acid copolymer dispersion; microcrystalline cellulose; povidone (polyvidone) K-30; sodium hydroxide; starch (corn); talc; triethyl citrate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Diclofenac/misoprostol is a combination product containing diclofenac, a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory and antipyretic properties, and misoprostol, a GI mucosal protective prostaglandin E1 analog.
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 is a synthetic prostaglandin E1 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 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.
General pharmacokinetic characteristics
The pharmacokinetic profiles of diclofenac and misoprostol administered as the fixed combination Arthrotec delayed-release tablets, 50 mg/0.2 mg or Arthrotec delayed-release tablets, 75 mg/0.2 mg are similar to the profiles when the two drugs are administered as separate tablets. 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 to 400 mcg. Neither diclofenac nor misoprostol accumulated in plasma following repeated doses of Arthrotec given every 12 hours under fasted conditions.
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 to 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 delayed-release tablets, 50 mg/0.2 mg and Arthrotec delayed-release tablets, 75 mg/0.2 mg.
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 less than 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.
Diclofenac: 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: It undergoes rapid and extensive metabolism to its biologically active metabolite, misoprostol acid.
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.
Age: Geriatric Population
A 4-week study, comparing plasma level profiles of diclofenac (50 mg two times a day) in younger adults (26 to 46 years, N=10) versus elderly subjects (66 to 81 years, N=10), did not show differences between age groups. In subjects over 64 years of age, the AUC for misoprostol acid was increased.
In a multiple-dose crossover study of 24 elderly subjects aged 65 years or older, the misoprostol contained in Arthrotec (two times a day) did not affect the pharmacokinetics of diclofenac.
Age: Pediatric Population
Diclofenac and misoprostol have not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been identified.
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 varying degrees of renal impairment showed an approximate doubling of elimination half-life, Cmax, and AUC compared to healthy subjects.
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
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.
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies to evaluate the potential for carcinogenesis and animal studies to evaluate the effects on fertility have been performed with each component of Arthrotec given alone.
The carcinogenicity potential of Arthrotec and misoprostol has not been studied in animals. In a 24 month rat carcinogenicity study, misoprostol administered orally at doses up to 2.4 mg/kg/day was not tumorigenic. In a 21 month mouse carcinogenicity study, misoprostol administered orally at doses up to 16 mg/kg/day (48 mg/m2/day), 80 times the recommended maximum human dose based on body surface area, was not tumorigenic.
In a 24 month rat carcinogenicity study, Arthrotec administered orally at up to 2 mg/kg/day (12 mg/m2/day) was not tumorigenic. In a 24 month mouse carcinogenicity study, oral Arthrotec at doses up to 0.3 mg/kg/day (0.9 mg/m2/day, 0.006 times the recommended maximum human dose based on body surface area) in males and 1 mg/kg/day (3 mg/m2/day, 0.02 times the recommended maximum human dose based on body surface area) in females was not tumorigenic.
Arthrotec combinations in 250:1 ratio was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the rat lymphocyte chromosome aberration test, or the mouse bone marrow micronucleus test.
Impairment of Fertility
The effects of Arthrotec and misoprostol on male or female fertility have not been studied in animals; however, there are data with Arthrotec given alone. Misoprostol, when administered to male and female breeding rats in an oral dose range of 0.1 to 10 mg/kg/day (0.6 to 60 mg/m2/day, 1 to 100 times the recommended maximum human dose based on body surface area) produced dose-related pre- and postimplantation losses and a significant decrease in the number of live pups born at the highest dose (60 mg/m2/day, 100 times the recommended maximum human dose based on body surface area). Arthrotec at oral doses up to 4 mg/kg/day (24 mg/m2/day, 0.16 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.
13.2 Animal Toxicology
A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse during long-term toxicology studies with misoprostol. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol.
14 CLINICAL STUDIES
Arthrotec, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of osteoarthritis.
Arthrotec, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of rheumatoid arthritis.
Upper gastrointestinal safety
Diclofenac, and other NSAIDs, have caused serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine. Misoprostol has been shown to reduce the incidence of endoscopically diagnosed NSAID-induced gastric and duodenal ulcers. In a 12-week, randomized, double-blind, dose-response study, misoprostol 200 mcg administered four, three or two times a day, was significantly more effective than placebo in reducing the incidence of gastric ulcer in OA and RA patients using a variety of NSAIDs. The three times a day regimen was therapeutically equivalent to misoprostol 200 mcg four times a day with respect to the prevention of gastric ulcers. Misoprostol 200 mcg given two times a day was less effective than 200 mcg given three or four times a day. The incidence of NSAID-induced duodenal ulcer was also significantly reduced with all three regimens of misoprostol compared to placebo.
Results of a study in 572 patients with osteoarthritis demonstrate that patients receiving Arthrotec have a lower incidence of endoscopically defined gastric ulcers compared to patients receiving Arthrotec.
16 HOW SUPPLIED/STORAGE AND HANDLING
NDC: 63629-4970-1 20 TABLET, DELAYED RELEASE in a BOTTLE
NDC: 63629-4970-2 14 TABLET, DELAYED RELEASE in a BOTTLE
NDC: 63629-4970-3 60 TABLET, DELAYED RELEASE in a BOTTLE
NDC: 63629-4970-4 30 TABLET, DELAYED RELEASE in a BOTTLE
NDC: 63629-7034-1 30 TABLET, DELAYED RELEASE in a BOTTLE
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or their caregivers of the following information before initiating therapy with Arthrotec delayed-release tablets and periodically during the course of ongoing therapy.
Premature Closure of the Fetal Ductus Arteriosus
Diclofenac may cause premature closure of the fetal ductus arteriosus. Arthrotec delayed-release tablets are contraindicated in pregnant women [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1) ].
Advise females of reproductive potential that Arthrotec delayed-release tablets may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Use in Specific Populations (8.3) ].
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1) ].
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2) ].
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Arthrotec delayed-release tablets and seek immediate medical therapy [see Warnings and Precautions (5.3) ].
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5) ].
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7) ].
Serious Skin Reactions
Advise patients to stop Arthrotec delayed-release tablets immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9) ].
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of Arthrotec delayed-release tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7) ]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use of NSAIDS and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with Arthrotec delayed-release tablets until they talk to their healthcare provider [see Drug Interactions (7) ].
Actavis Laboratories FL, Inc.
Fort Lauderdale, FL 33314 USA
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
Revised: May 2016
Medication Guide for
Arthrotec (dye kloe’ fen ak soe’ dee um) and Misoprostol (mye’ soe pros’ tol)
A combination of diclofenac a Nonsteroidal Anti-inflammatory Drug (NSAID) and misoprostol a GI mucosal protective prostaglandin E 1 analog
What is the most important information I should know about Arthrotec delayed-release tablets ?
Do not take Arthrotec delayed-release tablets if you are pregnant. Arthrotec can cause abortion, premature birth, birth defects, and uterine rupture.
What is the most important information I should know about medicines containing Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?
NSAIDs can cause serious side effects, including:
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
The risk of getting an ulcer or bleeding increases with:
NSAID containing medicines should only be used:
○ exactly as prescribed
○ at the lowest dose possible for your treatment
○ for the shortest time needed
What are NSAIDs?
NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.
Who should not take NSAID containing medicines?
Do not take NSAIDs:
Before taking Arthrotec delayed-release tablets , tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all of the medicines you take, including prescription or over - the-counter medicines, vitamins or 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)? ”
Get emergency help right away if you get any of the following symptoms:
Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:
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
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.
Actavis Laboratories FL, Inc.
Fort Lauderdale, FL 33314 USA
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
For more information, go to www.actavis.com or call 1-800-272-5525
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: May 2016
Diclofenac/Misoprostol DR 75/0.2mg
Diclofenac Sod./Misoprostol DR 50/0.2
Arthrotec pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Arthrotec available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Arthrotec destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Arthrotec Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Arthrotec pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Arthrotec?
Depending on the reaction of the Arthrotec after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Arthrotec not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Arthrotec addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Reviewsdrugs.com conducted a study on Arthrotec, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Arthrotec consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
Visitor reported usefulNo survey data has been collected yet
Visitor reported side effectsNo survey data has been collected yet
Visitor reported price estimatesNo survey data has been collected yet
Visitor reported frequency of useNo survey data has been collected yet
Visitor reported dosesNo survey data has been collected yet
Visitor reported time for resultsNo survey data has been collected yet
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The information was verified by Dr. Arunabha Ray, MD Pharmacology