Sapropterin Other names: Tetrahydrobiopterin

Safety and efficacy of sapropterin in patients with renal or hepatic insufficiency have not been established. Caution must be exercised when prescribing to such patients.

BH4 is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of sapropterin with all medicinal products that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil.

Caution should be exercised when prescribing sapropterin to patients receiving treatment with levodopa. Cases of convulsion, exacerbation of convulsion, increased excitability and irritability have been observed during co-administration of levodopa and sapropterin in BH4-deficient patients.

Although concomitant administration of inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim) has not been studied, such medicinal products may interfere with BH4 metabolism. Caution is recommended when using such medicinal products while taking sapropterin.

There are limited amount of data from the use of sapropterin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Available disease-associated maternal and/or embryofoetal risk data from the Maternal Phenylketonuria Collaborative Study on a moderate amount of pregnancies and live births (between 300-1,000) in PKU-affected women demonstrated that uncontrolled phenylalanine levels above 600 μmol/l are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies.

Maternal blood phenylalanine levels must therefore be strictly controlled before and during pregnancy. If maternal phenylalanine levels are not strictly controlled before and during pregnancy, this could be harmful to the mother and the foetus. Physician-supervised restriction of dietary phenylalanine intake prior to and throughout pregnancy is the first choice of treatment in this patient group.

The use of sapropterin should be considered only if strict dietary management does not adequately reduce blood phenylalanine levels. Caution must be exercised when prescribing to pregnant women.

It is not known whether sapropterin or its metabolites are excreted in human breast milk. Sapropterin should not be used during breast-feeding.

Fertility

In preclinical studies, no effects of sapropterin on male and female fertility were observed.

Sapropterin has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Approximately 35% of the 579 patients aged 4 years and over who received treatment with sapropterin dihydrochloride (5 to 20 mg/kg/day) in the clinical trials for sapropterin experienced adverse reactions. The most commonly reported adverse reactions are headache and rhinorrhoea.

In a further clinical trial, approximately 30% of the 27 children aged below 4 years who received treatment with sapropterin dihydrochloride (10 or 20 mg/kg/day) experienced adverse reactions. The most commonly reported adverse reactions are “amino acid level decreased” (hypophenylalaninaemia), vomiting and rhinitis.

List of adverse reactions

In the pivotal clinical trials and in the post-marketing experience for sapropterin, the following adverse reactions have been identified.

The following definitions apply to the frequency terminology used hereafter: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Immune system disorders

Not known: Hypersensitivity reactions (including serious allergic reactions) and rash

Metabolism and nutrition disorders

Common: Hypophenylalaninaemia

Nervous system disorders

Very common: Headache

Respiratory, thoracic and mediastinal disorders

Very common: Rhinorrhoea

Common: Pharyngolaryngeal pain, nasal congestion, cough

Gastrointestinal disorders

Common: Diarrhoea, vomiting, abdominal pain, dyspepsia, nausea

Not known: Gastritis, oesophagitis

Paediatric population

Frequency, type and severity of adverse reactions in children were essentially similar to those in adults.