DAXAS

Indications

• Chronic obstructive pulmonary disease (COPD)
• Chronic bronchitis with a history of frequent exacerbations

Dosage

Children: Roflumilast is not indicated for use in children; refer to the BNF for Children for information on alternative treatments.

Adults: Refer to the BNF for specific dosing recommendations for adults, typically administered as a once-daily oral tablet.

Mechanism of action

Roflumilast and its active metabolite, roflumilast N-oxide, inhibit phosphodiesterase-4 (PDE4), an enzyme responsible for the breakdown of cyclic adenosine monophosphate (cAMP). By inhibiting PDE4, roflumilast leads to increased intracellular levels of cAMP, which is associated with anti-inflammatory effects in the lungs. The precise mechanisms through which these effects are mediated are not fully defined.

Pharmacodynamics

Roflumilast increases the levels of cyclic adenosine monophosphate (cAMP) in targeted cells by selectively inhibiting PDE4, which is crucial in mediating inflammatory responses. The drug is highly selective for PDE4 and does not significantly affect other phosphodiesterases (PDEs), ensuring a focused therapeutic effect.

Pharmacokinetics

Roflumilast is administered orally, and it undergoes extensive hepatic metabolism, primarily via cytochrome P450 1A2 and 3A4 pathways. Its half-life allows for once-daily dosing. Roflumilast and its metabolites are primarily excreted via the urine. The pharmacokinetics may be influenced by liver function, necessitating caution in patients with hepatic impairment.

Adverse effects

• Cough
• Headache
• Pneumonia
• Infection (such as tuberculosis, viral hepatitis, herpes infection)
• Eosinophilic rhinitis
• Throat irritation
• Arthralgia
• Nausea
• Rash
• Decreased appetite
• Diarrhea
• Gastrointestinal discomfort
• Insomnia
• Weight decrease
• Anxiety
• Asthenia
• Back pain
• Dizziness
• Gastrointestinal disorders
• Malaise
• Muscle complaints
• Muscle weakness
• Palpitations
• Skin reactions
• Tremor
• Vertigo
• Vomiting
• Angioedema
• Constipation
• Depression
• Haematochezia
• Respiratory tract infection
• Suicidal behaviors
• Taste altered

Interactions

• Aminophylline: Severe (increases exposure)
• Theophylline: Severe (increases exposure)
• Mexiletine: Unknown (increases exposure)
• Mitotane: Unknown (decreases exposure)
• Osilodrostat: Unknown (increases exposure)
• Rucaparib: Unknown (increases exposure)
• SSRIs: Unknown (increases exposure)
• Vemurafenib: Unknown (increases exposure)

Precautions

• Moderate to severe cardiac failure
• Severe acute infectious disease
• History of psychiatric illness (discontinue if new or worsening psychiatric symptoms occur)
• Eosinophilic disease
• Severe immunological disease

Pregnancy

Not known to be harmful. Can be taken as normal during pregnancy.

Breast-feeding

Unlikely to be present in milk. Can be taken as normal during breastfeeding.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Oral solution
• Capsule

Mechanism of action

Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of PDE4. Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic 3′,5′-adenosine monophosphate (cyclic AMP) metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP. The specific mechanism(s) by which roflumilast exerts its therapeutic action is not well defined.

Pharmacodynamics

Roflumilast and its active metabolite, roflumilast N-oxide, increase cyclic adenosine-3′, 5′-monophosphate (cAMP) in affected cells by inhibiting PDE4. They are highly selective for PDE4 and are effectively inactive against PDEs 1, 2, 3, 5, and 7.