DICLOFENAC SODIUM/MISOPROSTOL DICLOFENAC-SODIUM-MISOPROSTOL- diclofenac sodium/misoprostol tablet

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

DICLOFENAC SODIUM (UNII: QTG126297Q) (DICLOFENAC - UNII:144O8QL0L1), MISOPROSTOL (UNII: 0E43V0BB57) (MISOPROSTOL - UNII:0E43V0BB57)

Available from:

Preferred Pharmaceuticals Inc.

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Diclofenac sodium and misoprostol delayed-release tablets are indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in adult 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 ( 5.3)] . Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in the following patients: Risk Summary Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women [see Contraindications ( 4)]. If a woman becomes pregnant while taking diclofenac sodium and misoprostol delayed-release tablets, discontinue the drug and advise the woman of the potential risks to her and to a fetus. There are no adequate and well-controlled studies of diclofenac sodium and misoprostol delayed-release tablets in pregnant women; however, there is information available about the active drug components of diclofenac sodium and misoprostol delayed-release tablets, diclofenac sodium and misoprostol. Administration of misoprostol to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects [see Warnings and Precautions ( 5.1)] . 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 a component of diclofenac sodium and misoprostol delayed-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment ( 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 diclofenac sodium and misoprostol 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations 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 eighth week of pregnancy. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. Diclofenac sodium and misoprostol 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. Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women [see Contraindications ( 4)]. 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.     Fetal/Neonatal Adverse Reactions Misoprostol 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 (misoprostol is not approved for this use). Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in pregnant women [see Contraindications ( 4)].   Diclofenac Premature Closure of Fetal Ductus Arteriosus: NSAIDs, including diclofenac, can cause premature closure of the fetal ductus arteriosus at about 30 weeks gestation and later in pregnancy (see Data) . Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including diclofenac, at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment (see Data) .   Labor or Delivery There are no studies on the effects of diclofenac sodium and misoprostol delayed-release tablets or diclofenac during labor or delivery. In animal studies, NSAIDS, including diclofenac, 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. The risk of uterine rupture associated with misoprostol use in pregnancy may occur at any gestational age, and increases with advancing gestational age and with prior uterine surgery, including cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture. Data   Human Data Misoprostol 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.   Diclofenac Data from observational studies regarding potential embryo-fetal risks of NSAID use (including diclofenac) in the first or second trimesters of pregnancy are inconclusive. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data The reproductive and developmental effects of both the combination of diclofenac sodium and misoprostol and each component of diclofenac sodium and misoprostol 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, diclofenac sodium and misoprostol delayed-release tablets was administered at dose combinations (diclofenac and misoprostol, 250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m 2 /day, 0.8 times the MRHD based on body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m 2 /day, 0.8 times the MRHD 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/m 2 /day, 16 times the MRHD based on body surface area) and pregnant rabbits at doses up to 1.0 mg/kg/day (12 mg/m 2 /day, 20 times the MRHD based on body surface area), there was no evidence of teratogenicity. In oral teratology studies with diclofenac sodium in pregnant mice at doses up to 20 mg/kg/day (60 mg/m 2 /day, 0.4 times the MRHD based on body surface area), pregnant rats at doses up to 10 mg/kg/day (60 mg/m 2 /day, 0.4 times the MRHD based on body surface area) and pregnant rabbits at doses up to 10 mg/kg/day (120 mg/m 2 /day, 0.8 times the MRHD based on body surface area), there was no evidence of teratogenicity. Risk Summary No lactation studies have been conducted with diclofenac sodium and misoprostol delayed-release tablets; however, limited published literature reports that diclofenac and the active metabolite of misoprostol are present in breast milk [see Clinical Pharmacology ( 12.3)] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium and misoprostol delayed-release tablets and any potential adverse effects on the breastfed infant from the diclofenac sodium and misoprostol delayed-release tablets or from the underlying maternal condition. Diclofenac sodium and misoprostol delayed-release tablets are not recommended in women of childbearing potential [see Warnings and Precautions ( 5.1)] . If diclofenac sodium and misoprostol delayed-release tablets are prescribed, patients must be advised of the abortifacient property and warned not to give the drug to others. Pregnancy Testing Verify pregnancy status for females of reproductive potential within 2 weeks prior to initiating  diclofenac sodium and misoprostol delayed-release tablets. Contraception Females Diclofenac sodium and misoprostol delayed-release tablets can cause fetal harm when administered to a pregnant woman [see Contraindications ( 4) and Use in Specific Populations ( 8.1)]. Advise females of reproductive potential to use effective contraception during treatment with diclofenac sodium and misoprostol delayed-release tablets. Diclofenac sodium and misoprostol delayed-release tablets may be prescribed if the patient: Safety and effectiveness of diclofenac sodium and misoprostol delayed-release tablets in pediatric patients have not been established. Geriatric patients (those 65 years of age and older), compared to younger adult patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions [see Warnings and Precautions ( 5.2, 5.3, 5.7)] . In addition, the risk of diclofenac-associated adverse reactions may be greater in geriatric patients with renal impairment or those taking concomitant ACE inhibitors or ARBs [see Drug Interactions ( 7) and Use in Specific Populations ( 8.6)] . Avoid use of diclofenac sodium and misoprostol delayed-release tablets in geriatric patients with cardiovascular and/or renal risk factors. If use cannot be avoided, use the lowest recommended dosage for the shortest duration and monitor for cardiac and renal adverse reactions [see Dosage and Administration ( 2.1)] . Monitor renal function in geriatric patients during treatment with diclofenac sodium and misoprostol delayed-release tablets, especially in patients with concomitant use of ACE inhibitors or ARBs . Of the 2,184 patients in clinical studies with diclofenac sodium and misoprostol delayed-release tablets, 557 (25.5%) were 65 years of age and over. No overall differences in effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in effectiveness between geriatric patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. No clinically meaningful differences in the pharmacokinetics of diclofenac and misoprostol were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology ( 12.3)]. Diclofenac and misoprostol are primarily excreted by the kidney. Long-term administration of NSAIDs has resulted in renal toxicity. Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium and misoprostol delayed-release tablets. Monitor renal function, especially during concomitant use of ACE inhibitors or ARBs. Also, monitor renal function in patients with hepatic impairment. Avoid the use of diclofenac sodium and misoprostol delayed-release tablets in patients with advanced renal disease. If use cannot be avoided in patients with advanced renal disease, use the lowest dosage for the shortest duration, monitor the patient’s renal function and monitor for clinical signs of worsening renal function [ see Warnings and Precautions ( 5.7), Drug Interactions ( 7) and Clinical Pharmacology ( 12.3) ].

Product summary:

Diclofenac sodium and misoprostol delayed-release tablets, USP are supplied as a uncoated tablets in dosage strengths of either 50 mg diclofenac sodium/200 mcg misoprostol or 75 mg diclofenac sodium/200 mcg misoprostol. The dosage strengths are supplied in: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

DICLOFENAC SODIUM/MISOPROSTOL DICLOFENAC-SODIUM-MISOPROSTOL-
DICLOFENAC SODIUM/MISOPROSTOL TABLET
PREFERRED PHARMACEUTICALS INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
DICLOFENAC SODIUM
AND MISOPROSTOL DELAYED-RELEASE TABLETS SAFELY AND EFFECTIVELY. SEE
FULL PRESCRIBING
INFORMATION FOR DICLOFENAC SODIUM AND MISOPROSTOL DELAYED-RELEASE
TABLETS.
DICLOFENAC SODIUM AND MISOPROSTOL DELAYED-RELEASE TABLETS, FOR ORAL
USE
INITIAL U.S. APPROVAL: 1997
WARNING: RISK OF UTERINE RUPTURE, ABORTION, PREMATURE BIRTH, BIRTH
DEFECTS;
SERIOUS CARDIOVASCULAR EVENTS; AND SERIOUS GASTROINTESTINAL EVENTS
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
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INDICATIONS AND USAGE
Diclofenac sodium and misoprostol delayed-release tablets are a
combination of diclofenac sodium, a
non-steroidal anti-inflammatory drug, and misoprostol, a
prostaglandin-1 (PGE1) analog, indicated for the
treatment of signs and symptoms of osteoarthritis or rheumatoid
arthritis in adult patients at high risk of
developing NSAID-induced gastric and duodenal ulcers and their
complications. ( 1)
DOSAGE AND ADMINISTRATION
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DOSAGE FORMS AND STRENGTHS
Delayed-release tablets:
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ADMINISTRATION OF MISOPROSTOL, A COMPONENT OF DICLOFENAC SODIUM AND
MISOPROSTOL
DELAYED-RELEASE TABLETS, TO PREGNANT WOMEN CAN CAUSE UTERINE RUPTURE,
ABORTION,
PREMATURE BIRTH, OR BIRTH DEFECTS. UTERINE RUPTURE HAS OCCURRED WHEN
MISOPROSTOL
WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR AN ABORTION. (
4, 5.1, 8.1)
DICLOFENAC SODIUM AND MISOPROSTOL DELAYED-RELEASE TABLETS ARE
CONTRAINDICATED IN
PREGNANCY AND IS NOT RECOMMENDED IN WOMEN OF CHILDBEARING POTENTIAL.
PATIENTS
MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE
THE DRUG TO
OTHERS. ( 5.1, 8.3)
INCREASED RISK OF SERIOUS CARDIOVASCULAR THROMBOTIC EVENTS, INCLUDING
MYOCARDIAL
INFARCTION AND STROKE, WHICH CAN BE FATAL. ( 5.2)
DICLOFENAC SODIUM AND MISOPROSTOL DELAYED-RELEASE TABLETS ARE
CONTRAI