Cataflam Use In Pregnancy & Lactation

Pregnancy: Risk summary: There are insufficient data on the use of diclofenac in pregnant women. Some epidemiological studies suggest an increased risk of miscarriage after use of a prostaglandin synthesis inhibitor (such as NSAIDs) in early pregnancy, however the overall data are inconclusive. Diclofenac has been shown to cross the placental barrier in humans. Use of NSAIDs, including diclofenac, can cause uterine inertia, premature closure of the fetal ductus arteriosus and fetal renal impairment leading to oligohydramnios. Because of these risks, Cataflam should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risks to the fetus.
In addition, Cataflam should not be used during the third trimester of pregnancy (see Contraindications).
Sugar-coated tablets: In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac daily during the period of organogenesis at doses up to approximately 0.41, 0.41, and 0.81 times, respectively, the maximum recommended human dose (MRHD) of Cataflam, despite the presence of maternal and fetal toxicity (see Animal data as follows).
Oral drops: In animals, administration of a prostaglandin synthetase inhibitor has been shown to result in increased pre-implantation and post-implantation loss and embryofetal lethality. In addition, increased incidences of various malformations, including cardiovascular malformations, have been reported in animals given a prostaglandin synthetase inhibitor during organogenesis (see Animal data as follows).
Clinical considerations: Fetal Adverse Drug Reactions: Premature Closure of Fetal Ductus Arteriosus: As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of premature closure of the fetal ductus arteriosus (see Contraindications).
Oligohydramnios/Fetal Renal Impairment: Risk of fetal renal impairment with subsequent oligohydramnios has been observed when NSAIDs (including diclofenac) were used from the 20^th week of pregnancy onwards.
If an NSAID is necessary from the 20^th week gestation to the end of the 2^nd trimester, limit the use to the lowest effective dose and shortest duration possible (see Dosage & Administration). If Cataflam treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue Cataflam and follow up according to clinical practice.
Labor or Delivery: There are no studies on the effects of Cataflam during labor or delivery. As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of uterine inertia (see Contraindications).
Sugar-coated tablets: In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Data: Human Data: Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs during the third trimester of pregnancy may cause premature closure of the fetal ductus arteriosus.
Oligohydramnios/Fetal Renal Impairment: Published studies and post-marketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal impairment leading to oligohydramnios. 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.
Animal Data: Sugar-coated tablets: Reproductive and developmental studies in animals demonstrated that diclofenac 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 (0.41 times the maximum recommended human dose [MRHD] of Cataflam, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (0.41 and 0.81 times, respectively, the MRHD based on BSA comparison).
In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.08 and 0.16 times the MRHD based on BSA) from Gestation Day 15 through Lactation Day 21, significant maternal mortality (caused by gastrointestinal ulceration and peritonitis) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, intrauterine growth retardation, and decreased fetal survival.
Administration of NSAIDs (including diclofenac) inhibited ovulation in the rabbit and implantation and placentation in the rat and led to premature closure of the fetal ductus arteriosus.
Oral drops: Additional studies indicate that, with repeated oral doses in rats (>1 mg/kg body weight), diclofenac causes effects that influence fertility (lower testosterone level, and decreased epididymal and testicular weight in association with histopathological changes). Similar effects were also observed in the F1 generation following doses of ≥1.25 mg/kg in a two-generation study. In dogs, daily subcutaneous doses of 2 mg/kg diclofenac sodium led to an increased spermatid count. Further studies describe a decreased mating frequency in female rats following a repeated dose of ≥0.5 mg/kg diclofenac. For this reason, an influence on both male and female fertility cannot be ruled out.
Diclofenac crosses the placental barrier in rodents. Administration of NSAIDs (including diclofenac) inhibited ovulation in rabbits and implantation and placentation in rats, and led to premature closure of the ductus arteriosus in pregnant rats. Maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, decreased fetal survival, and intrauterine growth retardation in rats. The slight effects of diclofenac on reproduction parameters and delivery as well as closure of the ductus arteriosus in utero are pharmacological effects of this class of prostaglandin synthetase inhibitors (see Contraindications).
In a study in mice, teratogenicity (cleft palate) was observed at the maternally toxic dose of 4 mg/kg. In rats and rabbits, doses up to the maternally toxic level did not lead to teratogenic effects. Delayed ossification and reduced fetal weight in a study in rabbits were the only changes observed in these investigations.
At maternally toxic doses, the perinatal and post-natal development of the offspring were impaired (see fertility, also birth weight and delayed post-natal growth as previously mentioned).
Lactation: Risk Summary: Like other NSAIDs, diclofenac passes into the breast milk in small amounts. Therefore, Cataflam should not be administered during breast-feeding in order to avoid undesirable effects in the infant.
Human Data: Diclofenac was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother treated orally with a diclofenac salt of 150 mg/day. The estimated dose ingested by an infant consuming breast milk is equivalent to 0.03 mg/kg/day.
Females and males of reproductive potential: Female fertility: As with other NSAIDs, the use of Cataflam may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Cataflam should be considered.
Male fertility: There is no human data on the effect of Cataflam on male fertility.
Sugar-coated tablets: Diclofenac administered to male and female rats at 4 mg/kg/day (approximately 0.16 times the MRHD based on BSA comparison) did not affect fertility.
Oral drops: In animals, based on relevant data, impairment of male fertility cannot be ruled out (see Animal data as previously mentioned). The relevance of this finding for humans is unclear.