Pharmacokinetics in children

The PK of children is comparable to that of adults [SmPC NutropinAq] [FDA Humatrope].

In adults, the following PK parameters apply:

In children, the following PK parameters apply:

* Calculated with ln2 / Ka (=0.122)

There is substantial inter-individual variability in growth hormone (GH) PK among children, while intra-individual variation is less pronounced [Houdijk 1997] [Lundberg 2018]. After SC administration, absorption may be somewhat slower in children, resulting in a later peak concentration and sometimes a longer apparent half-life (5.6 hours) due to flip-flop kinetics; however, overall systemic exposure remains predictable with weight-based dosing. According to the PopPK study, increased body weight is associated with decreased dose-normalized GH exposure. When accounting for the influence of body weight, no additional differences in PK were found between children and adults [Papathanasiou 2021].

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Common (1-10%): peripheral edema. Arthralgia, myalgia.

Uncommon (0.1-1%): stiffness in extremities. Headache, benign intracranial hypertension, paresthesia.

Rare (0.01-0.1%): hypertension. Insomnia.

Also reported: epiphysiolysis of the femoral head and Legg-Calvé-Perthes disease; it is unclear whether these side effects are related to the underlying condition or to treatment with somatropin. Cases of leukemia have been reported in children with GH deficiency; however, there is no evidence that the incidence of leukemia is increased without the presence of predisposing factors.

[Dutch Farmacotherapeutisch Kompas]

Mild scoliosis was reported in two pubertal children with ACAN mutations [Renes 2024].

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Initiation of treatment and monitoring should always be carried out by a pediatric endocrinologist (or nephrologist if the indication is chronic renal insufficiency). The primary parameters for assessing the effectiveness of growth hormone therapy are the change in height SDS and growth velocity. IGF-I levels are essential for monitoring biological response and guiding dose adjustments [Wakeling 2017]. Clinicians should always refer to local or national protocols for the appropriate monitoring of metabolic and other relevant parameters, as recommendations may differ between guidelines and should be tailored to the specific indication.

Alternate injection sites to avoid tissue changes such as lipoatrophy or lipohypertrophy [SmPC Omnitrope].

Serum cortisol may decrease with somatropin treatment; previously undiagnosed central (secondary) hypoadrenalism may be identified, and glucocorticoid replacement therapy may be required.

Monitor thyroid function in all patients. Somatropin increases peripheral deiodination of T4 to T3 and may thus reveal incipient hypothyroidism. In patients with hypothyroidism, closely monitor standard replacement therapy when treating with somatropin.

Perform fundoscopy for papilledema in cases of severe or recurrent headaches, visual problems, nausea, and/or vomiting. If papilledema is present, consider the possibility of benign intracranial hypertension and discontinue growth hormone therapy if necessary. Careful monitoring is required when resuming therapy.

During treatment, monitor for symptoms of glucose intolerance. Use caution in diabetes mellitus because of diabetogenic effect of growth hormone; a higher dose of insulin may be required after initiation of somatropin therapy. Treatment with somatropin is not indicated in diabetics with active proliferative or severe nonproliferative retinopathy.

If edema or severe paresthesia persists, reduce the dose to prevent development of carpal tunnel syndrome.

If there is no response, antibodies should be determined and, if titers are rising, binding capacity should also be determined.

A small number of children with growth hormone deficiency have been reported to have leukemia; however, there is no evidence that the incidence of leukemia is increased without the presence of predisposing factors, e.g., radiation to the head or brain.

In a history of childhood cancer, treatment with somatropin increases the likelihood of a second neoplasm; intracranial tumors (particularly meningiomas) may particularly occur in patients who have received radiation to the head for their first neoplasm. In the event of complete remission of a malignancy, carefully monitor for a possible recurrence after treatment with growth hormone is started.

In cases of growth hormone deficiency due to an intracranial lesion, regularly examine for progression of the condition.

Epiphysiolysis of the femoral head may occur more frequently in individuals with endocrine disorders, including growth hormone deficiency, than in the general population. Limping and hip or knee pain may indicate this condition.

Consider pancreatitis (although rare) when abdominal pain occurs, especially in children.

During treatment, check for signs of scoliosis as this can worsen in any rapidly growing child.

Increased mortality compared to placebo has been demonstrated in patients with acute life-threatening conditions due to complications of open-heart surgery, abdominal surgery, multiple trauma caused by an accident, or acute respiratory failure who were treated with high-dose somatropin (5.3-8 mg/day). The safety of continuing growth hormone supplementation in the presence of a concurrent acute life-threatening condition has not been established.

[Dutch Farmacotherapeutisch Kompas]

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

References

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