INVAROX FILM COATED TABLET 15MG [SIN16977P]

Product Info

INVAROX FILM COATED TABLET 15MG

[SIN16977P]

4.1 Indications

Adults
INVAROX is indicated for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
There are limited data on the relative effectiveness of rivaroxaban and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled (see section ‘Pharmacodynamic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

INVAROX is indicated for the treatment of Deep Vein Thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT, PE in adults (See section ‘Special warnings and precautions for use’ for haemodynamically unstable PE patients – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Paediatric population

INVAROX 15 MG
Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents aged less than 18 years and weighing from 30kg to 50 kg after at least 5 days of initial parenteral anticoagulation treatment.

INVAROX 20 MG
Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents aged less than 18 years and weighing more than 50 kg after at least 5 days of initial parenteral anticoagulation treatment.

4.2 Dosage and method of administration

Posology

Prevention of stroke and systemic embolism in adults
The recommended dose is 20 mg once daily, which is also the recommended maximum dose.

If a dose is missed the patient should take INVAROX immediately and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in adults
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE.

Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of therapy should be considered in patients with provoked DVT or PE not related to major transient risk factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.

When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with INVAROX 10 mg once daily, a dose of INVAROX 20 mg once daily should be considered.

The duration of therapy and dose selection should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section ‘Special warnings and precautions for use’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

It is essential to adhere to the dosage schedule provided.

If a dose is missed during the 15 mg twice daily treatment phase, the patient should take INVAROX immediately to ensure intake of 30 mg INVAROX per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.

If a dose is missed during the once daily treatment phase, the patient should take INVAROX immediately to ensure intake of the recommended daily dose. The patient should continue with the regular once daily dose intake as recommended on the following day.

Treatment of VTE and prevention of VTE recurrence in children and adolescents
INVAROX treatment in children and adolescents aged less than 18 years should be initiated following at least 5 days of initial parenteral anticoagulation treatment (see section ‘Pharmacodynamic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).
The dose for children and adolescent is calculated based on body weight.

• Body weight of 50 kg or more:
  a once daily dose of 20 mg rivaroxaban is recommended. This is the maximum daily dose.

• Body weight from 30 to 50 kg:
  a once daily dose of 15 mg rivaroxaban is recommended. This is the maximum daily dose.

The weight of a child should be monitored and the dose reviewed regularly. This is to ensure a therapeutic dose is maintained. Dose adjustments should be made based on changes in body weight only.

Treatment should be continued for at least 3 months in children and adolescents. Treatment can be extended up to 12 months when clinically necessary. There is no data available in children to support a dose reduction after 6 months treatment. The benefit-risk of continued therapy after 3 months should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential bleeding risk.

If a dose is missed, the missed dose should be taken as soon as possible after it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed. The patient should not take two doses to make up for a missed dose.

Intake of INVAROX in relation to food
INVAROX 15mg and INVAROX 20 mg tablets are to be taken with food (see section ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Converting from Vitamin K Antagonists (VKA) to INVAROX

• Prevention of stroke and systemic embolism:
  VKA treatment should be stopped and INVAROX therapy should be initiated when the INR is ≤ 3.0.

• Treatment of DVT, PE and prevention of recurrence in adults and treatment of VTE and prevention of recurrence in paediatric patients:
  VKA treatment should be stopped and INVAROX therapy should be initiated once the INR is ≤ 2.5.

When converting patients from VKAs to INVAROX, INR values will be falsely elevated after the intake of INVAROX. The INR is not valid to measure the anticoagulant activity of rivaroxaban, and therefore should not be used (see section ‘Interaction with other medicinal products and other forms of interaction’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Converting from INVAROX to Vitamin K antagonists (VKA)
There is a potential for inadequate anticoagulation during the transition from rivaroxaban to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that rivaroxaban can contribute to an elevated INR.

No clinical trial data are available to guide converting patients from rivaroxaban to warfarin. rivaroxaban affects INR, so INR measurements made during co-administration with warfarin may not be useful for determining the appropriate dose of warfarin.

One approach is to discontinue INVAROX and begin both a parenteral anticoagulant and warfarin at the time the next dose of INVAROX would have been taken.
In another approach, in patients converting from INVAROX to VKA, VKA should be given concurrently until the INR is ≥2.0. For the first two days of the conversion period, standard VKA dosing should be used followed by VKA dosing guided by INR testing. While patients are on both INVAROX and VKA, the INR should not be tested earlier than 24 h (after the previous dose but prior to the next dose of INVAROX). Once INVAROX is discontinued INR testing may be done reliably 24 h after the last dose (see sections ‘Interaction with other medicinal products and other forms of interaction’ and ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Patients are to be carefully monitored for signs of bleeding complications during the conversion period.

Paediatric patients:
Children who convert from INVAROX to VKA need to continue INVAROX for 48 hours after the first dose of VKA. After 2 days of co-administration an INR should be obtained prior to the next scheduled dose of INVAROX. Co-administration of INVAROX and VKA is advised to continue until the INR is ≥ 2.0. Once INVAROX is discontinued INR testing may be done reliably 24 hours after the last dose (see above and section ‘Interaction with other medicinal products and other forms of interaction’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Converting from parenteral anticoagulants to INVAROX
For adult and paediatric patients currently receiving a parenteral anticoagulant, start INVAROX 0 to 2 hours before the time of the next scheduled administration of the parenteral drug (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral drug (e.g. intravenous unfractionated heparin).

Converting from INVAROX to parenteral anticoagulants
Discontinue INVAROX and give the first dose of parenteral anticoagulant at the time the next INVAROX dose would be taken.

Cardioversion

Rivaroxaban can be initiated or continued in patients who may require cardioversion.

For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, INVAROX treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see sections ‘Pharmacodynamic Properties’ and ‘Pharmacokinetic Properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Additional information on special populations

Patients with renal impairment

Adults:
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 – 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, INVAROX is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections ‘Special warnings and precautions for use’ and ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

In patients with moderate (creatinine clearance 30 – 49 ml/min) or severe (creatinine clearance 15 – 29 ml/min) renal impairment the following dosage recommendations apply:

• For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

• For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: patients should be treated with 15 mg twice daily for the first 3 weeks. Thereafter, when the recommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient’s assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and has not been studied in this clinical setting (see sections ‘Special warnings and precautions for use’, ‘Pharmacodynamic properties’ and ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).
  When the recommended dose is 10 mg once daily, no dose adjustment from the recommended dose is necessary.

No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 – 80 ml/min) (see section ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Paediatric population:

• Children and adolescents with mild renal impairment (glomerular filtration rate 50 – 80 mL/min/1.73 m²): no dose adjustment is required, based on data in adults and limited data in paediatric patients (see section ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

• Children and adolescents with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m²): rivaroxaban is not recommended as no clinical data is available (see section ‘Special warnings and precautions for use’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Patients with hepatic impairment
INVAROX is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections ‘Contraindications’ and ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).
No clinical data is available in children with hepatic impairment.

Geriatric patients
No dose adjustment.

Body weight
No dose adjustment for adults.
For paediatric patients the dose is determined based on body weight.

Gender
No dose adjustment.

Children and adolescents
The safety and efficacy of rivaroxaban in children aged 0 to < 18 years have not been established in the indication prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. No data are available. Therefore, it is not recommended for use in children below 18 years of age in indications other than the treatment of VTE and prevention of VTE recurrence.
SPAF: Patients who undergo PCI (percutaneous coronary intervention) with stent placement
There is limited experience of a reduced dose of 15mg rivaroxaban once daily (or 10mg rivaroxaban once daily for patients with moderate renal impairment [creatinine clearance 30 – 49 ml/min]) in addition to a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulation and undergo PCI with stent placement (see section ‘Warning and precautions for use’, ‘Pharmacodynamic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Method of administration
Adults
For oral use.

Crushing of tablets
For patients who are unable to swallow whole tablets, INVAROX tablet may be crushed and mixed with water or soft foods such as applesauce immediately prior to use and administered orally. After the administration of crushed INVAROX 15 mg or INVAROX 20 mg tablets, the dose should be immediately followed by food.

The crushed INVAROX tablet may be given through gastric tubes. Gastric placement of the tube should be confirmed before administering INVAROX. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. After the administration of crushed INVAROX 15 mg or 20 mg tablets, the dose should then be immediately followed by enteral feeding (see section ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Children and adolescents weighing 30kg to 50 kg
INVAROX is for oral use.
The patient should be advised to swallow the tablet with liquid. It should also be taken with food (see section ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). The tablets should be taken approximately 24 hours apart.

In case the patient immediately spits up the dose or vomits within 30 minutes after receiving the dose, a new dose should be given. However, if the patient vomits more than 30 minutes after the dose, the dose should not be re-administered and the next dose should be taken as scheduled.

The tablet must not be split in an attempt to provide a fraction of a tablet dose.

Crushing of tablets
When doses of 15 mg or 20 mg rivaroxaban are prescribed, these could be provided by crushing the 15 mg or 20 mg tablet and mixing it with water or apple puree immediately prior to use and administering orally.
The crushed tablet may be given through a nasogastric or gastric feeding tube (see sections ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Clinically significant active bleeding.

Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section ‘Pharmacokinetic properties’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Pregnancy and lactation (see section ‘Pregnancy and lactation’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Lesion or condition if considered to be a significant risk of major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.

Concomitant treatment with any other anticoagulant agent e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, etc.) except under the circumstances of switching therapy to or from rivaroxaban (see section ‘Dosage and method of administration’) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter. (see section ‘Interaction with other medicinal products and other forms of interaction’ – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information)