Safety

Arthrotec (diclofenac sodium/misoprostol) Oral Tablets

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

May 2016

Summary View

BOXED WARNING

WARNING: RISK OF UTERINE RUPTURE, ABORTION, PREMATURE BIRTH, BIRTH DEFECTS; AND SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

ARTHROTEC CONTAINS DICLOFENAC SODIUM 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 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 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 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 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.
  • ARTHROTEC is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
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.

CONTRAINDICATIONS

ARTHROTEC is contraindicated in the following patients:

  • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium/misoprostol, other prostaglandins, or any components of the drug product.
  • 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.
  • In the setting of coronary artery bypass graft (CABG) surgery.
  • Pregnancy. Use of ARTHROTEC during pregnancy can result in maternal and fetal harm, including abortion, premature birth, birth defects, and uterine rupture.
  • Active gastrointestinal bleeding.

WARNINGS AND PRECAUTIONS

Hypertension
  • Add angiotensin converting enzyme (ACE) inhibitors.

The following sections all include extensive updates, please refer to label:

  • Cardiovascular Thrombotic Events
    • Status Post Coronary Artery Bypass Graft (CABG) Surgery
    • Post-MI Patients
  • Gastrointestinal Bleeding, Ulceration, and Perforation
    • Risk Factors for GI Bleeding, Ulceration, and Perforation
    • Strategies to Minimize the GI Risks in NSAID-treated patients
  • Hepatotoxicity
  • Heart Failure and Edema
  • Renal Toxicity and Hyperkalemia
  • Anaphylactic Reactions
  • Exacerbation of Asthma Related to Aspirin Sensitivity
  • Serious Skin Reactions
  • Premature Closure of Fetal Ductus Arteriosis
  • Hematologic Toxicity
  • Masking of Inflammation and Fever
  • Laboratory Monitoring

ADVERSE REACTIONS

The following sections all include extensive updates, please refer to label:

  • Clinical Trials Experience
    • Clinical Trials Experience with {product name}
  • Post Marketing Experience

DRUG INTERACTIONS

  • There has been updated information added, in table formation, please refer to label.

USE IN SPECIFIC POPULATIONS

  • Label has been updated to reflect PLLR conversion

PATIENT INFORMATION

  • This section has been updated extensively, please refer to label.

MEDICATION GUIDE

  • This section has been updated extensively, please refer to label.

 

April 2015

Summary View

WARNINGS

Hepatic Effects
  • In another clinical trial where over 17,000 patients received diclofenac for a mean of 18 months, hepatitis was rarely observed.
  • In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and usually occur within 1-6 months, but can occur at any time during treatment with diclofenac.

ADVERSE REACTIONS

Metabolic and Nutritional
  • oalanine aminotransferase and aspartate aminotransferase increased

 

September 2014

Summary View

CONTRAINDICATIONS

  • add contraindication for patients with active gastrointestinal bleeding

WARNINGS

  • add that the use of diclofenac/misoprostol with concomitant NSAIDs including COX-2 inhibitors should be avoided.

expand Skin Reactions subsection

PRECAUTIONS

  • remove statement that nursing mothers should not take Arthrotec
Drug Interactions
  • revise statement about renal function in Ace Inhibitors subsection
  • add Tacrolimus subsection
  • add data to Nursing Mothers subsection

ADVERSE REACTIONS

add the following subsections:

  • Pregnancy, puerperium and perinatal conditions
  • Congenital, familial and genetic disorders
  • expand upon the following subsections:
  • Body as Whole
  • Female Reproductive Disorders
  • Hemic and lymphatic system subsection
  • Metabolic and nutritional subsection
  • Skin and appendages subsection
  • Urinary subsection

PATIENT INFORMATION

  • Clarify that caution should be exercised in nursing mothers
  • Add that broken tablets should not be taken

 

March 2013

Summary View

Drug Interactions

CYP2C9 inhibitors
  • Use caution when dosing diclofenac with CYP2C9 inhibitors (e.g. voriconazole). Concomitant use of CYP2C9 inhibitors may enhance toxicity of diclofenac due to an increase in systemic exposure to diclofenac. When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of  diclofenac should not exceed the lowest recommended dose of ARTHROTEC 50 twice daily (see DOSAGE AND ADMINISTRATION).
Voriconazole:
  • In a published study, 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 2.1-fold and 1.8-fold respectively when coadministered with voriconazole compared to diclofenac alone.
CYP2C9 inducers
  • Use caution when dosing diclofenac with CYP2C9 inducers (e.g. rifampin). Concomitant use of CYP2C9 inducers may lead to compromised efficacy due to a decrease in systemic exposure to diclofenac. The separate products of misoprostol and diclofenac should be used if a higher dose of diclofenac is deemed necessary.
     

 

December 2010

Summary View

PRECAUTIONS

Voriconazole
  • In a published study, single dose diclofenac (50 mg) was coadministered with the last dose of voriconazole (400 mg every12 hours on Day 1, followed by 200 mg every 12 hours on Day 2). The mean Cmax and AUC of diclofenac were increased by 2.1-fold and 1.8- fold respectively when coadministered with voriconazole compared to diclofenac alone.

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