Roflumilast

Registered South African indications:

• Chronic obstructive airway disease (moderate to severe)
  - Associated with chronic bronchitis in patients at risk of exacerbations

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Moderate to severe hepatic impairment (Child-Pugh Classes B & C)

Cautions

• Pregnancy
• Breastfeeding
• Mild hepatic impairment (Child-Pugh Class A)
• Porphyria
• Body weight <60kg
• Severe immunological disease
  - HIV infection
  - Multiple sclerosis
  - Lupus erythematosus
  - Progressive multifocal leukoencephalopathy
• Severe acute infectious diseases
• Cancers (except basal cell carcinoma)
• Patients being treated with immunosuppressive medicinal products (except short-term systemic corticosteroids)
• Latent infections
  - Tuberculosis
  - Viral hepatitis
  - Herpes viral infection
  - Herpes zoster
• Congestive heart failure (NHYA grade 3 and 4)
• History of depression associated with suicidal ideation or behaviour
• Previous or existing psychiatric symptoms
• Persistent intolerability
• Black, non-smoking females
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: tab

Chronic obstructive pulmonary disease 
- Maintenance treatment of severe chronic obstructive pulmonary disease (FEV1 post-bronchodilator <50% predicted) associated with chronic bronchitis in patients with a history of frequent exacerbations as add on to bronchodilator treatment

• Oral (tab): Initial: 250μg, dly for 28 days; Maintenance: 500μg, daily

This starting dose is intended to reduce adverse reactions and patient discontinuation when initiating therapy, but it is a sub-therapeutic dose. Therefore, the 250μg dose should be used only as a starting dose

Roflumilast 500μg may need to be taken for several weeks to achieve its full effect. Roflumilast 500μg has been studied in clinical trials for up to one year and is intended for maintenance treatment

Roflumilast is not indicated as a rescue medicinal product for the relief of acute bronchospasms

There are no clinical data to support concomitant treatment with theophylline for maintenance therapy. Therefore, the concomitant treatment with theophylline is not recommended

Not established for use in children below 18 years

Pregnancy

• Caution; not recommended
• There are limited data from the use of roflumilast in pregnant women
• Studies in animals have shown reproductive toxicity. Roflumilast has been demonstrated to cross the placenta in pregnant rats
• Women of childbearing age should be advised to use an effective method of contraception during treatment. Roflumilast is not recommended in women of childbearing potential not using contraception. Roflumilast is not recommended during pregnancy

Breastfeeding

• Caution; not recommended
• Available pharmacokinetic data in animals have shown excretion of roflumilast or its metabolites in milk. A risk to the breastfed infant cannot be excluded. Roflumilast should not be used during breastfeeding

Fertility

• In a human spermatogenesis study, roflumilast 500μg had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period

Renal Impairment

• No dose adjustment recommended 

Hepatic Impairment

• Mild (Child-Pugh Class A): Caution; no information available
  Clinical data for these patients is insufficient to recommend a dose adjustment and caution should be exercised in these patients
• Moderate to severe (Child-Pugh Classes B & C): Contraindicated

Elderly

• No dose adjustment recommended

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Tremor
• Vertigo
• Dizziness
• Insomnia
• Anxiety
• Suicidal ideation
• Suicidal behaviour
• Depression
• Nervousness
• Panic attack
• Asthenia

Cardiovascular Disorders

• Palpitations

Respiratory Disorders

• Respiratory tract infections (excluding pneumonia)

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Gastritis
• Gastroesophageal reflux disease
• Dyspepsia
• Haematochezia
• Constipation

Hepatobiliary Disorders

• Increased gamma-glutamyltransferase
• Increased aspartate aminotransferase

Endocrine and Metabolic Disorders

• Gynaecomastia
• Decreased weight
• Decreased appetite

Musculoskeletal Disorders

• Muscle spasms
• Muscle weakness
• Myalgia
• Back pain
• Increased blood creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Angioedema

Sensory Disorders

• Dysgeusia

• CYP1A2 inhibitors
• Enoxacin
• CYP3A4 inhibitors
• Erythromycin
• Ketoconazole
• CYP2C19 inhibitors
• Cimetidine
• Fluvoxamine
• CYP450 inducers
• Rifampicin
• Phenobarbital
• Carbamazepine
• Phenytoin
• Theophylline

• Weight

None routine. Specific cases may require

• Hepatic function

Roflumilast is a PDE4 inhibitor, a non-steroid, anti-inflammatory active substance designed to target both the systemic and pulmonary inflammation associated with COPD. The mechanism of action is the inhibition of PDE4, a major cyclic adenosine monophosphate (cAMP)-metabolizing enzyme found in structural and inflammatory cells important to the pathogenesis of COPD. Roflumilast targets the PDE4A, 4B and 4D splicing variants with similar potency in the nanomolar range. The affinity to the PDE4C splicing variants is 5 to 10-fold lower. This mechanism of action and the selectivity also apply to roflumilast N-oxide, which is the major active metabolite of roflumilast.

Tablet 500μg

• Daxas (Astrazeneca) originator