Medicinal Products

ADEMPAS 2.5 mg

Generic drug of the therapeutic class: Cardiology and angiology
active ingredients: Riociguat
laboratory: Bayer Pharma AG

Coated tablet
Box of 90
All forms

Indication

Chronic Thromboembolic Pulmonary Hypertension (HTP-TEC)

Adempas is indicated in adult patients in WHO functional class II to III with

• an inoperable HTP-TEC,

• Persistent or recurrent HTP-TEC after surgical treatment,
in order to improve exercise capacity (see section on Pharmacodynamic properties).

Pulmonary Arterial Hypertension (PAH)

Adempas alone or in combination with an endothelin receptor antagonist is indicated in adult patients with pulmonary arterial hypertension (PAH) in WHO functional class II to III in order to improve exercise capacity.

Efficacy has been demonstrated in patients with PAH, including idiopathic, heritable or associated with connective tissue disease (see section 5.1).

Dosage ADEMPAS 2.5 mg Film-coated tablet Box of 90

Treatment should only be initiated and supervised by a physician experienced in the treatment of HTP-TEC or PAH.

Dosage

Dosage Adjustment P hase

The recommended starting dose is 1 mg three times daily for 2 weeks, with an interval of approximately 6 to 8 hours between doses (see section 5.2 ).

The dose will then be increased from 0.5 mg three times a day every 2 weeks up to the maximum dose of 2.5 mg three times a day, if the systolic blood pressure is ≥ 95 mmHg and if the patient presents no signs or symptoms of hypotension. In some patients on PAH, the 1.5 mg dose three times a day may be sufficient to achieve an adequate response in terms of distance to the 6-minute walk test (CT6) (see section 5.1).

In the event of a decrease in systolic blood pressure to 95 mmHg, if the patient has no signs or symptoms of hypotension, the dose will be maintained; if the patient has signs or symptoms of hypotension, the dose should be reduced by 0.5 mg three times daily.

Maintenance dose

The individual dose established after the dose adjustment phase will be maintained unless signs and symptoms of hypotension occur, in which case it should be decreased.

The daily dose should not exceed 7.5 mg (2.5 mg 3 times daily).

If they are forgotten, treatment will be continued by taking the next dose at the usual time.

In case of intolerance, a reduction of the dose should be considered.

Food intake

The tablets can be taken during or without meals. Nevertheless, plasma concentrations of riociguat may be higher on fasting compared to mealtime (see section 5.2 ). Therefore, as a precautionary measure, the switch from taking Adempas during the meal to taking Adempas outside of meals is not recommended especially in patients at risk of hypotension.

Interruption of treatment

In case of interruption for 3 days or more, the treatment will be reinstated at a dose of 1 mg three times a day for 2 weeks followed by a gradual increase according to the regimen recommended during the dosage adjustment phase of treatment ( see above).

Special populations

The individual dosage adjustment at the initiation of the treatment makes it possible to adjust the dose for each patient.

Pediatric population

The safety and efficacy of riociguat in children and adolescents under 18 years of age have not been established. No clinical data is available. Non-clinical data showed effects on bone growth (see section 5.3 ). The significance in humans of these results observed in animals is not known. Therefore, in the current state of the data, the use of riociguat should be avoided in growing children and adolescents (see Warnings and Precautions ).

Elderly

In elderly people (65 years or older), the risk of hypotension is higher. Therefore, individual dose adjustment should be performed with caution (see section 5.2 ).

Hepatic insufficiency

Adempas has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). In the absence of data, its use is contraindicated in these patients (see Contraindications section ).

An increase in systemic exposure to riociguat has been observed in patients with moderate hepatic impairment (Child-Pugh Class B) (see section 5.2 ). Therefore, individual dosage adjustment should be performed with caution in these patients.

Renal failure

Data are limited in patients with severe renal impairment (creatinine clearance <30 ml / min) and none are available in dialysis patients. As a result, the use of Adempas is not recommended in these patients (see Warnings and Precautions ).

In patients with moderate renal impairment (creatinine clearance <50 to 30 ml / min), the systemic exposure to riociguat is higher (see section 5.2). The risk of hypotension is higher in patients with renal impairment. Individual dosage adjustment should be done with caution.

Agitated tab

Smokers are strongly advised to stop smoking because of the risk of a weaker response to treatment. The plasma concentrations of riociguat are reduced in smokers compared to nonsmokers. An increase in osmosis up to the maximum dose of 2.5 mg three times daily may be required in smokers or patients who start to smoke during treatment (see sections Interactions with other drugs and other forms of interactions and pharmacokinetic properties ).

A decrease in dosage may be necessary for patients who stop smoking.

Administration mode

Oral way.

Against indications

- Concomitant treatment with phosphodiesterase-5 inhibitors (IPDE-5) such as sildenafil, tadalafil, vardenafil (see section 4.5). See also Interactions with other medicinal products and other forms of interaction

- severe hepatic insufficiency (Child-Pugh class C)

- Hypersensitivity to the active substance or to any of the excipients (see section Composition ).

- Pregnancy (see section on Pregnancy and lactation ).

- Concomitant treatment with nitrated derivatives or products known as "nitric oxide donors" (eg amyl nitrite) in any form (see section Interactions with other medicinal products and other forms of interaction ) .

- Systolic blood pressure <95 mmHg at initiation of treatment.

Adempas side effects

Tolerance Profile Summary

The tolerability of Adempas has been evaluated in phase III studies in 681 patients with HTP-TEC or PAH who received at least one dose of riociguat (see section 5.1).

Most of the side effects are related to the relaxing effect on vascular smooth muscle or gastrointestinal tract.

The most commonly reported adverse reactions, occurring in ≥ 10% of Adempas-treated patients (up to 2.5 mg three times daily), were: headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea, and vomiting.

Cases of severe hemoptysis and pulmonary hemorrhage (such as bronchoalveolar haemorrhage, bronchial haemorrhage ...), including cases of fatal outcome, have been observed in patients with HTP-TEC or PAH treated with Adempas (see section Warnings and precautions for use ).

The safety profile of Adempas appeared similar in patients with HTP-TEC or PAH. Therefore, the adverse events (AEs) identified in the 12- and 16-week placebo-controlled clinical trials are presented by clustered frequencies in the table below (see Table 1).

Summary table of adverse effects:

The adverse effects reported with Adempas are presented in the table below by MedDRA system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100, <1/10), and uncommon (≥ 1/1000, <1/100).

Table 1: Adverse Reactions with Adempas in Phase III Clinical Studies

Classes of MedDRA Organ Systems Very common Frequent Rare
Infections and infestations Gastroenteritis
Blood and lymphatic system disorders Anemia (including the corresponding biological results)
Nervous system disorders Dizziness sensation Headache
Heart conditions palpitations
Vascular disorders hypotension
Respiratory, thoracic and mediastinal disorders H Emoptysis Epistaxis Nasal Congestion Pulmonary hemorrhage *
Gastrointestinal disorders Dyspepsia Diarrhea Nausea Vomiting Gastritis Gastro Esophageal Reflux, Dysphagia, Gastrointestinal and Abdominal Pain, Constipation, Abdominal Distention
General disorders and administration site conditions Peripheral edema

* cases of fatal pulmonary hemorrhage have been reported in the non-controlled long-term extension studies

Declaration of suspected adverse effects

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals report any suspected adverse reactions via the national reporting system - see Annex V *.

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