None known.
Not applicable
None.
Nureflex Kinder solution must not be in contact with any acidic solution such as certain antibiotics or diuretics. A rinse of the infusion line must be performed between each product administration.
No relevant information additional to that already contained elsewhere in the SmPC.
No relevant information, additional to that contained elsewhere in the SPC.
None stated.
There are no preclinical data considered relevant to clinical safety beyond data included in other sections of this Summary of Product Characteristics. With the exception of an acute toxicity study, no further studies have been carried out in juvenile animals with Nureflex Kinder.
Nureflex Kinder is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.
Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.
The half life of Nureflex Kinder is about 2 hours.
In limited studies, Nureflex Kinder appears in the breast milk in very low concentrations.
Ibuprofen is rabidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.
Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.
Elimination half-life is approximately 2 hours.
In limited studies, ibuprofen appears in the breast milk in very low concentrations.
The pharmacokinetic profile of Nureflex Kinder compared with that of conventional-release 400mg tablets showed that the sustained-release formulation reduced the peaks and troughs characteristic of the conventional-release tablets and gave higher levels at 5, 10, 15 and 24 hours. Compared with conventional-release tablets, the area under the plasma concentration time curve for sustained-release tablets was almost identical.
Both mean plasma profiles and the pre-dose plasma levels showed no major differences between the young and elderly age groups. In several studies, Nureflex Kinder produced a double peak plasma profile when taken under fasting conditions. The elimination half-life of ibuprofen is approximately 2 hours. Ibuprofen is metabolised in the liver to two inactive metabolites and these, together with unchanged ibuprofen, are excreted by the kidney either as such or as conjugates. Excretion by the kidney is both rapid and complete. Ibuprofen is extensively bound to plasma proteins.
Ibuprofen is a racemic mixture of [-]R- and [+]S-isomers. In vivo and in vitro studies indicate that the [+]S-isomer is responsible for clinical activity. The [-]R-form, while thought to be pharmacologically inactive, is slowly and incompletely (~60%) interconverted into the active [+]S species in adults. The [-]R-isomer serves as a circulating reservoir to maintain levels of active drug. The pharmacokinetic parameters of Nureflex Kinder determined in a study with volunteers are presented below.
Table 4: Pharmacokinetic Parameters of Intravenous Ibuprofen
| 400 mg* Nureflex Kinder Mean (CV%) | 800 mg* Nureflex Kinder Mean (CV%) | |
| Number of Patients | 12 | 12 |
| AUC (mcg•h/mL) | 109.3 (26.4) | 192.8 (18.5) |
| Cmax (mcg/mL) | 39.2 (15.5) | 72.6 (13.2) |
| KEL (1/h) | 0.32 (17.9) | 0.29 (12.8) |
| T½ (h) | 2.22 (20.1) | 2.44 (12.9) |
| AUC = Area-under-the-curve Cmax = Peak plasma concentration CV = Coefficient of Variation KEL = First-order elimination rate constant T½ = Elimination half-life * = 60 minute infusion time |
The pharmacokinetic parameters of Nureflex Kinder determined in a study with febrile pediatric patients are presented in Table 5. It was observed that the median Tmax was at the end of the infusion and that Nureflex Kinder had a shorter elimination half-life in pediatric patients compared to adults. The volume of distribution and clearance increased with age.
Table 5: Pharmacokinetic Parameters of 10 mg/kg Intravenous Ibuprofen, Pediatric Patients, by Age Group
| 6 months to < 2 years Mean (CV%) | 2 years to < 6 years Mean (CV%) | 6 years to 16 years Mean (CV%) | |
| Number of Patients | 5 | 12 | 25 |
| AUC (mcgh/mL) | 71.1 (37.1) | 79.2 (37.0) | 80.7 (36.9) |
| Cmax (mcg/mL) | 59.2 (34.8) | 64.2 (34.3) | 61.9 (26.6) |
| Tmax (min)* | 10 (10-30) | 12 (10-46) | 10 (10-40) |
| T½ (h) | 1.8 (29.9) | 1.5 (41.8) | 1.55 (26.4) |
| Cl (mL/h) | 1172.5 (38.9) | 1967.3 (56.0) | 4878.5 (71.0) |
| Vz (mL) | 2805.7 (20.1) | 3695.8 (30.0) | 10314.2 (67.4) |
| Cl/WT# (mL/hr/kg) | 133.7 (58.6) | 130.1 (82.4) | 109.2 (41.6) |
| Vz/WT# (mL/kg) | 311.2 (35.4) | 227.2 (41.7) | 226.8 (30.4) |
| *Median (minimum-maximum) #WT: body weight (kg) |
Ibuprofen, like most NSAIDs, is highly protein bound ( > 99% bound at 20 mcg/mL). Protein binding is saturable, and at concentrations > 20 mcg/mL binding is nonlinear. Based on oral dosing data, there is an age- or fever-related change in volume of distribution for ibuprofen.
Distribution
Although a great variability is observed in the premature population, peak plasma concentrations are measured around 35-40 mg/l after the initial loading dose of 10 mg/kg as well as after the last maintenance dose, whatever gestational and postnatal age. Residual concentrations are around 10-15 mg/l 24 hours after the last dose of 5 mg/kg.
Plasma concentrations of the S-enantiomer are much higher than those of the R-enantiomer, which reflects a rapid chiral inversion of the R- to the S-form in a proportion similar to adults (about 60%).
The apparent volume of distribution is on average 200 ml/kg (62 to 350 according to various studies). The central volume of distribution may depend on the status of the ductus and decrease as the ductus closes.
In vitro studies suggest that, similarly to other NSAIDs, ibuprofen is highly bound to plasma albumin, although this seems to be significantly lower (95 %) compared with adult plasma (99 %). Ibuprofen competes with bilirubin for albumin binding in newborn infant serum and, as a consequence, the free fraction of bilirubin may be increased at high ibuprofen concentrations.
Elimination
Elimination rate is markedly lower than in older children and adults, with an elimination half-life estimated at approximately 30 hours (16-43). The clearance of both enantiomers increases with gestational age, at least in the range of 24 to 28 weeks.
PK-PD relationship
In preterm newborns ibuprofen significantly reduced plasma concentrations of prostaglandins and their metabolites, particularly PGE2 and 6-keto-PGF-1-alpha. Low levels were sustained up to 72 hours in neonates who received 3 doses of ibuprofen, whereas subsequent re-increases were observed at 72 hours after only 1 dose of ibuprofen.
Not applicable.
Not applicable
None.
Administrative dataAs for all parenteral products, ampoules of Nureflex Kinder should be visually inspected for particulate matter and the integrity of the container prior to use. Ampoules are intended for single use only, any unused portions must be discarded.
Chlorhexidine must not be used to disinfect the neck of the ampoule as it is not compatible with the Nureflex Kinder solution. Therefore, for asepsis of the ampoule before use, ethanol 60% or isopropyl alcohol 70% is recommended.
When disinfecting the neck of the ampoule with an antiseptic, to avoid any interaction with the Nureflex Kinder solution, the ampoule must be completely dry before it is opened.
The required volume to be given to the infant should be determined according to body weight, and should be injected intravenously as a short infusion over 15 minutes, preferably undiluted.
Use only sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution to adjust injection volume.
The total volume of solution injected to preterm infants should take into account the total daily fluid volume administered. A maximal volume of 80 ml/kg/day on the first day of life should usually be respected; this should be progressively increased in the following 1-2 weeks (about 20 ml/kg birthweight/day) up to a maximal volume of 180 ml/kg birthweight/day.
Before and after administration of Nureflex Kinder, to avoid contact with any acidic solution, rinse the infusion line over 15 minutes with 1.5 to 2 ml of either sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%), solution for injection.
After first opening of an ampoule, any unused portions must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
