Analgesics, antiphlogistics and anesthetics

4.1.1

Paracetamol

The half-life of paracetamol is 2.6 hours, both in the mother’s plasma and milk, and the milk/plasma ratio is close to unity ( , ). After a single dose of 650 mg paracetamol to 12 nursing mothers, maximum milk concentrations were 10–15 mg/L recorded 1–2 hours post-dose. The maximum exposure for a fully breastfed infant would be 0.45 mg/kg, which corresponds to 4% of the weight-related therapeutic dose for infants ( ). Another study including three nursing mothers reported that after a single dose of 500 mg paracetamol, the maximum measured concentration in breast milk was 4.39 mg/L, and the authors estimated infant exposure to be less than 0.1% of maternal dose ( ). One report of adverse effects in the breast-fed infant has been reported to date: a case of reproducible maculopapular rash following a maternal dose of 1 g of paracetamol, suggesting causal association ( ). The concentration in breast milk was low and the dose ingested by the infant would only amount to 1 mg per feed. Further, one study including 43 infants whose mothers were treated with paracetamol were followed and no side effects were observed in any of the infants ( ). Even though drug metabolism is not fully developed in newborns, and an accumulation of paracetamol in the breastfed infant could theoretically be possible, it has not been reported. Paracetamol is used to treat pain and fever in neonates and it can even be given to premature infants ( ).

4.1.2

Acetylsalisylic acid

Only small amounts of acetylsalicylic acid (ASA) are excreted in milk, with a milk/plasma ratio of <0.1 ( ). Peak values in breast milk are reached in 2–6 hours post dose but may delay even more ( , ). In a study of five breastfeeding mothers the highest salicylate concentration in breast milk after a 500 mg dose was 7.8 mg/L, after a 1,000 mg dose was 21 mg/L, and after a 1,500 mg dose was 48 mg/L ( ).

One case report describes a 16-day old infant with serum concentrations of 240 mg/L salicylate suffering from tachypnea, metabolic acidosis and tachycardia. The mother used 3.9 g ASA daily. Because of the unexpectedly high drug concentration, the authors also considered the possibility that the child herself was given ASA ( ). Another case report describes a woman using 2.4 g ASA daily for rheumatic disease during pregnancy and postpartum. The child was born slightly preterm at 36 gestational weeks. At the age of 2 months, while only partially breast-fed, the infant serum salicylate concentration was nearly 30% of maternal drug concentration (0.47 mmol/L versus 1.63 mmol/L, respectively). The child did not have any symptoms. The authors concluded that the neonatal immature hepatic metabolism and renal excretion capacity might have predisposed to the high serum drug concentration ( ). In a study based maternal interviews, 15 mothers used ASA during breastfeeding and none of the infants were reported to have any symptoms; however, no data on dose or length of treatment was recorded ( ). In users, aspirin in analgesic doses (>500 mg/day) is associated with risk of platelet dysfunction and possibly also with Reye’s syndrome in children. Repeated analgesic doses should therefore be avoided during breastfeeding. Adverse effects would not be expected in the breastfed infant if the mother uses low-dose therapy (100–300 mg/day) or takes occasional analgesic doses.

4.1.3

Pyrazolone and phenylbutazone derivatives

Little documented experience exists on the use of drugs from this group during breastfeeding.

Dipyrone or metamizol is excreted in milk, the M/P-ratio being close to unity, including the four main metabolites ( ). Breast milk and plasma levels of dipyrone were investigated in eight lactating women after a single oral dose of 1.0 g. Concentration-time curves were presented for two mothers, indicating that the peak levels for the different metabolites occurred at 2–18 hours post-dose, and none of the metabolites were detected in milk samples after 48 hours ( ). One case report describes cyanotic attacks in an infant of a mother who had taken three doses of 500 mg dipyrone. A milk sample, and blood samples from both mother and infant were taken 24 hours after the last dose. The concentration of dipyrone in milk was 4.3 μg/mL, and the serum concentration was similar in the mother and the infant (3.3 μg/mL and 3.2 μg/mL, respectively) ( ). Dipyrone is no longer widely used due to the potential serious hematological adverse effects, as safer alternatives are available.

Phenylbutazone has a half-life of 30–170 hours. No detailed information on the passage to human milk is available. No adverse effects have been reported and the American Academic of Pediatrics (AAP) Committee on Drugs considers its occasional use compatible with breastfeeding ( ). However, due to the long half-life and the potentially serious adverse effects which include hematological disturbances and renal and liver toxicity, use during breast feeding is not justifiable. One report describes a case of hemolytic anemia in the breastfed infant when the mother was taking propyphenazone after delivery. Propyphenazone was detected in infant plasma during the acute phase of hemolysis, and could still be detected in the milk 8 days after stopping treatment ( ). Similarly to phenylbutazone, propyphenazone has been largely replaced by newer non-steroidal anti-inflammatory drugs (NSAIDs) with a more favorable safety profile.

No information on famprofazone and breast-feeding is available. Famprofazone is metabolized to metamphetamine and amphetamine. Use is contraindicated during breast feeding, as safer alternatives are available.

4.1.4

Non-steroidal anti-inflammatory drugs (NSAID)

Non-steroidal anti-inflammatory drugs (NSAIDs) are acidic, have limited lipofilicity and are highly plasma protein bound (up to 99%), resulting in low M/P-ratios. The AAP has evaluated that ibuprofen , naproxen , diclofenac , indomethacin , ketorolac , piroxicam , mefenamic acid and flufenamic acid are all compatible with breastfeeding ( ).

Ibuprofen has a half-life of 2 hours. Transfer to milk is minimal and no adverse events related to exposure via breast milk have been reported. Following daily administration of 800–1600 mg ibuprofen to 13 lactating women, no ibuprofen could be detected in the milk. The detection limit in the studies were 0.5 μg/mL and 1 μg/mL and, respectively ( , ). In a further report, 400 mg ibuprofen was given every 6–8 hours to a lactating woman for dental surgery, confirming minimal exposure to the infant ( ). Ibuprofen is also widely used in pediatrics.

The half-life for naproxen is 10–18 hours and much longer than for several other NSAIDs. In a study of a breastfeeding mother receiving long-term naproxen therapy (250–375 mg × 2), the maximum relative infant dose was calculated as 3.6% ( ). Another study based on maternal interviews included 20 mothers who used naproxen while breastfeeding ( ). Two of the mothers reported symptoms (slight sleepiness) in their children. However, no data on dose or length of treatment were reported, and no conclusions about causal association can be made on the basis of these results ( ).

Diclofenac has a short half-life (1–2 hours). No original data on transfer to milk have been published. However, due to the pharmacokinetic profile, exposure via breast milk is expected to be minimal and no adverse effects have been reported.

Indomethacin has a half-life of 4 hours. One study, including 16 mothers who received 75–300 mg indomethacin daily for several days during the postpartum period reported low drug transfer to milk (M/P ratio 0.37). Plasma concentration was measured in seven of the infants and was above the detection limit in only one infant, the highest weight-related dose calculated as 1% for any of the infants ( ). While exposure is probably minimal, the potential adverse effects on renal function, and the prolonged half-life of indomethacin in neonates and preterm infants make indomethacin less suitable for repeated use during breast feeding.

Keterolac has a half-life of 3–9 hours and is excreted into breast milk in small amounts. After 10 mg dose four times daily, the maximum milk concentration was 7.9 ng/mL, corresponding to a relative infant dose of 0.2%. In four out of ten mothers no ketorolac could be detected in milk ( ).

Piroxicam has a relatively long half-life of 30–60 hours. Small amounts are excreted in milk. Milk and plasma samples were analyzed in four women who received 20 mg piroxicam once a day for arthritis ( ). At steady state the relative infant dose was calculated to average 3.5% and at most 6.3% of the weight-related maternal dose ( ). A urine sample from one of the infants did not show any traces of piroxicam or its metabolites. Piroxicam is poorly absorbed from intact skin.

Flufenamic acid and mefenamic acid both have a short half-life, 2–3 hours. Minimal amounts of both drugs were detected in milk and infant serum in two studies both including ten mother/infant pairs, but using insensitive assay methods ( , ).

There are no data for etofenamate and breast feeding. Systemic absorption through intact skin is 20%.

Flurbiprofen has a half-life of 3 hours. In a study of 12 women given 100–200 mg flurbiprofen daily, only three milk samples from two women contained detectable drug concentrations, the highest level measured 0.08 mg/mL. This corresponds to maximal infant exposure of 0.012 mg/kg/day or 0.5% of the maternal dose per kg. No toxic effects have been reported ( , ).

Ketoprofen has a short half-life, 1.5–2.5 hours. Low levels of ketoprofen in mother’s milk were reported in a study where a combination of ketoprofen and nalbuphine was given to 18 mothers. The calculated relative infant dose of ketoprofen was 0.31% ( ). Tenoxicam has a long half-life of 42–100 hours and no apparent advantages over other NSAIDs. No published information on administration during breast feeding is available.

A single dose of tiaprofen 300 mg was given to three mothers in one study published only as an abstract. Transfer to milk was minimal and the relative infant dose was estimated as 1.7% ( ). No further conclusions can be made on the safety of tiaprofen use on the basis of this report.

There is no documented experience on the use of acemethacin , dexketoprofen , lornoxicam , meloxicam , nabumetone or proglumetacin during breastfeeding.

4.1.5