ADEMPAS Film-coated tablet Ref.[8516] Active ingredients: Riociguat

Treatment should only be initiated and monitored by a physician experienced in the treatment of CTEPH or PAH.

Posology

Starting dose

The recommended starting dose is 1 mg 3 times daily for 2 weeks. Tablets should be taken 3 times daily approximately 6 to 8 hours apart (see section 5.2).

Titration

Adult patients

Dose should be increased by 0.5 mg 3 times daily every two weeks to a maximum of 2.5 mg 3 times daily, if systolic blood pressure is ≥95 mmHg and the patient has no signs or symptoms of hypotension. In some PAH patients, an adequate response on the 6-minute walk distance (6MWD) may be reached at a dose of 1.5 mg 3 times a day (see section 5.1). If systolic blood pressure falls below 95 mmHg, the dose should be maintained provided the patient does not show any signs or symptoms of hypotension. If at any time during the up-titration phase systolic blood pressure decreases below 95 mmHg and the patient shows signs or symptoms of hypotension the current dose should be decreased by 0.5 mg 3 times daily.

Paediatric patients of 6 years of age or older

Adempas is available for pediatric use as a tablet for those with body weight ≥50 kg. Titration of riociguat dose is to be performed based on the patient’s systolic blood pressure and general tolerability at the discretion of the treating physician/healthcare provider. If systolic blood pressure is ≥90 mmHg for the 6 to <12 years age group or ≥95 mmHg for the 12 to <18 years age group and the patient has no signs or symptoms of hypotension, the dosage should be increased by 0.5 mg every 2 weeks to a maximum dose of 2.5 mg 3 times daily.

If systolic blood pressure falls below these specified levels the dosage should be maintained provided the patient does not show any signs or symptoms of hypotension. If at any time during the up-titration phase systolic blood pressure decreases below the specified levels, or the patient shows signs and symptoms of hypotension the current dose should be decreased by 0.5 mg 3 times daily. (See below for further information on other indications and other age groups)

Maintenance dose

The established individual dose should be maintained unless signs and symptoms of hypotension occur.

The maximum total daily dose is 7.5 mg (i.e., 2.5 mg 3 times daily) for adults and paediatric patients with body weight of at least 50 kg.

If a dose is missed, treatment should be continued with the next dose as planned.

If not tolerated, dose reduction should be considered at any time.

Treatment discontinuation

In case treatment has to be interrupted for 3 days or more, treatment should be restarted with 1 mg 3 times daily for 2 weeks and continued with the dose titration regimen as described above.

Transitioning between phosphodiesterase-5 (PDE5) inhibitors and riociguat

Sildenafil must be discontinued in adults and children at least 24 hours prior to administration of riociguat.

Tadalafil must be discontinued at least 48 hours in adults and 72 hours in children prior to administration of riociguat.

Riociguat must be discontinued in adults and children at least 24 hours prior to administration of a PDE5 inhibitor.

It is recommended to monitor for signs and symptoms of hypotension after any transition (see sections 4.3, 4.5 and 5.1).

Special populations

Individual dose titration at treatment initiation allows adjustment of the dose to the patient´s needs.

Elderly

In elderly patients (65 years or older) there is a higher risk of hypotension and therefore particular care should be exercised during individual dose titration (see section 5.2).

Hepatic impairment

Patients with severe hepatic impairment (Child Pugh C) have not been studied and therefore use of riociguat is contraindicated in these patients (see section 4.3). Patients with moderate hepatic impairment (Child Pugh B) showed a higher exposure to this medicinal product (see section 5.2).

Particular care should be exercised during individual dose titration.

No clinical data are available in children with hepatic impairment.

Renal impairment

Data in patients with severe renal impairment (creatinine clearance <30 mL/min) are limited and there are no data for patients on dialysis. Therefore, use of riociguat is not recommended in these patients (see section 4.4).

Patients with mild and moderate renal impairment (creatinine clearance <80 – 30 mL/min) showed a higher exposure to this medicinal product (see section 5.2). There is a higher risk of hypotension in patients with renal impairment, therefore particular care should be exercised during individual dose titration.

No clinical data are available in children with renal impairment.

Patients on stable doses of strong multi pathway CYP/P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitors

Coadministration of riociguat with strong multi pathway CYP and P-gp/BCRP inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) increases exposure to riociguat (see section 4.5). When initiating riociguat in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors, consider a starting dose of 0.5 mg 3 times a day to mitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and on treatment. Consider a dose reduction for patients on riociguat doses higher than or equal to 1.0 mg if the patient develops signs or symptoms of hypotension (see sections 4.4 and 4.5).

No clinical data is available in children receiving concomitant systemic treatment with strong CYP/P-gp and BCRP inhibitors.

Paediatric population

The safety and efficacy of riociguat have not been established in the following pediatric populations:

• Children aged <6 years (see section 4.1), because of safety concerns. Non clinical data show undesirable effects on growing bone (see section 5.3).
• Children with PAH aged 6 to <12 years with systolic blood pressure <90 mmHg at treatment initiation (see section 4.3).
• Children and adolescents with PAH aged 12 to <18 years with systolic blood pressure <95 mmHg at treatment initiation (see section 4.3).
• Children and adolescents with CTEPH aged <18 years old (see section 4.1).

No clinical trial data are available. Therefore, the use of riociguat is not recommended in these populations.

Smokers

Current smokers should be advised to stop smoking due to a risk of a lower response. Plasma concentrations of riociguat in smokers are reduced compared to non-smokers. A dose increase to the maximum daily dose of 2.5 mg 3 times daily may be required in patients who are smoking or start smoking during treatment (see sections 4.5 and 5.2).

A dose decrease may be required in patients who stop smoking.

Method of administration

For oral use.

Food

Tablets can generally be taken with or without food. For patients prone to hypotension, as a precautionary measure, switches between fed and fasted riociguat intake are not recommended because of increased peak plasma levels of riociguat in the fasting compared to the fed state (see section 5.2).

Crushed tablets

For patients who are unable to swallow whole tablets, Adempas tablets may be crushed and mixed with water or soft foods, such as apple sauce, immediately prior to use and administered orally (see section 5.2).

In adults, inadvertent overdosing with total daily doses of 9 to 25 mg riociguat between 2 to 32 days was reported. Adverse reactions were similar to those seen at lower doses (see section 4.8).

In case of overdose, standard supportive measures should be adopted as required.

In case of pronounced hypotension, active cardiovascular support may be required.

Based on the high plasma protein binding riociguat is not expected to be dialysable.

3 years.

This medicinal product does not require any special storage conditions.

PP/Aluminium foil blister.

Pack sizes: 42, 84, 90 or 294 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.