Dyloject Injection

Pregnancy

Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.

Risk Summary

Use of NSAIDs, including DYLOJECT, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including DYLOJECT, in pregnant women starting at 30 weeks of gestation (third trimester).

There are no adequate and well-controlled studies of DYLOJECT in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss.

In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, and rabbits given diclofenac during the period of organogenesis at doses up to approximately 0.7, 0.7, and 1.3 times, respectively, the maximum recommended human dose (MRHD) of DYLOJECT despite the presence of maternal and fetal toxicity at these doses [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.

Clinical Considerations

Labor or Delivery

There are no studies on the effects of DYLOJECT during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Animal data

Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.7 times the maximum recommended human dose [MRHD] of DYLOJECT, 150 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.7 and 1.3 times, respectively, the MRHD based on BSA comparison). In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice, rats, and humans.

Lactation

Risk Summary

Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DYLOJECT and any potential adverse effects on the breastfed infant from the DYLOJECT or from the underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).

Females and Males of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including DYLOJECT, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. 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 DYLOJECT, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

The safety and efficacy of DYLOJECT has not been established in pediatric patients.

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)].

Diclofenac metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug 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.

The pharmacokinetics of DYLOJECT are similar in elderly compared to young adults [see Clinical Pharmacology (12.3)].

Hepatic Impairment

Orally administered diclofenac sodium is extensively metabolized. The pharmacokinetics of DYLOJECT are similar in patients with mild hepatic impairment compared to healthy subjects [see Clinical Pharmacology (12.3)]. Dosing adjustments in patients with mild hepatic impairment is not necessary. The pharmacokinetics of DYLOJECT were not studied in patients with moderate to severe hepatic impairment and use in this population is not recommended.

Renal Impairment

Pharmacokinetics of DYLOJECT in patients with mild to moderate renal impairment is similar compared to healthy subjects. However, acute renal decompensation was observed in 4% out of 68 patients enrolled with renal impairment and treated with DYLOJECT in clinical trials in the perioperative period. DYLOJECT is not recommended in patients with moderate to severe renal insufficiency and is contraindicated in patients with moderate to severe renal insufficiency in the perioperative period and who are at risk for volume depletion [see Contraindications (4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Body Weight

Pharmacokinetics of diclofenac following Dyloject Injection appear to be dependent on body weight. The effect of body weight on clinical efficacy and safety of DYLOJECT has not been fully studied. Therefore, adjusting dose based on body weight is not recommended [see Clinical Pharmacology (12.3)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.13 times the maximum recommended human dose [MRHD] of DYLOJECT, 150 mg/day, based on mg/m2 body surface area [BSA] comparison) have revealed no significant increase in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.01 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.04 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.

Mutagenesis

Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal aberration studies in Chinese hamsters.

Impairment of Fertility

Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.3 times the MRHD based on BSA comparison) did not affect fertility.

The effect of DYLOJECT in the short-term treatment of acute pain was evaluated in two double-blind, placebo and active-controlled, multiple-dose clinical trials in patients with postoperative pain. In both trials, intravenous morphine was permitted as rescue medication for pain management.

In a controlled, multiple-dose study of adult patients with postoperative pain who had undergone elective abdominal or pelvic surgery, 245 patients were treated with DYLOJECT, a positive NSAID control (ketorolac tromethamine), or placebo administered every 6 hours starting within 6 hours after surgery and for up to 5 days. The study population consisted of patients with a mean age of 43 years (range 18 to 65 years) and a minimum pain intensity of 50 mm on a 100-mm visual analog scale (VAS) at baseline. The mean baseline pain intensity on the VAS was 68 mm (range 50 to 100 mm). Approximately 63% of subjects in the DYLOJECT 37.5 mg group and 92% of subjects in the placebo group took rescue medication within the first 48 hours of the treatment phase. Efficacy was demonstrated by a reduction in pain intensity as measured by the sum of the pain intensity differences over 0 to 48 hours in patients receiving DYLOJECT as compared to placebo. The average pain intensities over time are depicted for the treatment groups in Figure 1.

In a second controlled, multiple-dose study of adult patients with postoperative pain who had undergone elective orthopedic surgery, 277 patients were treated with DYLOJECT, a positive NSAID control (ketorolac tromethamine), or placebo administered every 6 hours starting within 6 hours postsurgery and for up to 5 days. The study population consisted of patients with a mean age of 55 years (range 19 to 84 years) and a minimum pain intensity of 50 mm on a 100-mm VAS at baseline. The mean baseline pain intensity on the VAS was 69 mm (range 50 to 100 mm). Approximately 74% of subjects in the DYLOJECT group and 92% of subjects in the placebo group took rescue medication within the first 48 hours of the treatment phase. Efficacy was demonstrated by a reduction in pain intensity as measured by the sum of the pain intensity differences over 0 to 48 hours in patients receiving DYLOJECT as compared to placebo. The average pain intensities over time are depicted for the treatment groups in Figure 2.

Figure 1: Pain Intensity Score Versus Time                     Figure 2: Pain Intensity Score Versus Time

DYLOJECT (diclofenac sodium) Injection, is a clear, colorless solution that is supplied as a 1 mL fill in a clear 2 mL glass vial with an orange tamper-evident top.

Carton of 25 vials

Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature].

Do not freeze. Protect from light.

Keep DYLOJECT out of reach and sight of children.

Not made with natural rubber latex.

Inform patients, families, or their caregivers of the following information before initiating therapy with DYLOJECT and periodically during the course of ongoing therapy.

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)].

Hepatotoxicity

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 DYLOJECT 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)].

Anaphylactic Reactions

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 DYLOJECT immediately if they develop any type of rash, and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9)].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including DYLOJECT, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)].

Fetal Toxicity

Inform pregnant women to avoid use of DYLOJECT and other NSAIDs starting at 30 weeks gestation, because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of DYLOJECT 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 DYLOJECT until they talk to their healthcare provider [see Drug Interactions (7)].

                                                                                 EN-4307

Manufactured for:

Hospira, Inc., Lake Forest, IL 60045 USA