APIXABAN KRKA

Posology Prevention of stroke and systemic embolism in adult patients with non- valvular atrial fibrillation (NVAF) The recommended dose of apixaban is 5 mg taken orally twice daily. 5 mg/dL (133 micromole/L). Therapy should be continued long-term.

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) in adults The recommended dose of apixaban for the treatment of acute DVT and treatment of PE is 10 mg taken orally twice daily for the first 7 days followed by 5 mg taken orally twice daily.

, recent surgery, trauma, immobilisation). 5 mg taken orally twice daily. 4). 1). Treatment with apixaban in paediatric patients is based on weight-tiered dosing. The recommended dose of apixaban in paediatric patients weighing ≥ 35 kg is shown in Table 2.

Table 2:

Dose recommendation for treatment of VTE and prevention of recurrent VTE in paediatric patients weighing ≥ 35 kg Days 1-7 Day 8 and beyond Body weig ht (kg) Dosing schedu le Maximum daily dose Dosing schedu le Maximum daily dose ≥ 35 10 mg twice daily 20 mg 5 mg twice daily 10 mg For paediatric patients weighing < 35 kg, refer to the summary of product characteristics for apixaban granules in capsules for opening and apixaban coated granules in sachets.

4). Missed dose in adults and paediatric patients A missed morning dose should be taken immediately when it is noticed, and it may be taken together with the evening dose. A missed evening dose can only be taken during the same evening, the patient should not take two doses the next morning.

The patient should continue with the intake of the regular dose twice daily as recommended on the following day. 5). These medicinal products should not be administered simultaneously. Switching from vitamin K antagonist (VKA) therapy to Apixaban Krka When converting patients from vitamin K antagonist (VKA) therapy to Apixaban Krka, warfarin or other VKA therapy should be discontinued and Apixaban Krka started when the international normalised ratio (INR) is < 2.

Switching from Apixaban Krka to VKA therapy When converting patients from Apixaban Krka to VKA therapy, administration of Apixaban Krka should be continued for at least 2 days after beginning VKA therapy. After 2 days of coadministration of Apixaban Krka with VKA therapy, an INR should be obtained prior to the next scheduled dose of Apixaban Krka.

Coadministration of Apixaban Krka and VKA therapy should be continued until the INR is ≥ 2. 2). 2). 2). 5 mg/dL (133 micromole/L) associated with age ≥80 years or body weight ≤60 kg, a dose reduction is necessary (see above subheading Dose reduction).

2). 5 mg twice daily. 2). 2), no dose adjustment is necessary in paediatric patients with mild to moderate renal impairment. 4). Hepatic impairment Apixaban Krka is […]

1). Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 3 for adverse reaction profile and frequencies by indication). 6% in the apixaban vs acetylsalicylic acid study. 76%/year. 18%/year. 1). Tabulated list of adverse reactions Table 3 shows the adverse reactions ranked under headings of system organ class and frequency using the following convention: very common (≥ 1/10) common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data) in adults for NVAF and VTEp or VTEt and in paediatric patients from 28 days to < 18 years of age for VTEt and prevention of recurrent VTE.

The frequencies of adverse reactions reported in Table 3 for paediatric patients are derived from study CV185325, in which they received apixaban for treatment of VTE and prevention of recurrent VTE.

Table 3:

Tabulated adverse reactions System organ class Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF) Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt) in adult patients Treatment of VTE and prevention of recurrent VTE in paediatric patients from 28 days to less than 18 years of age.

Blood and lymphatic system disorders Anaemia Common Common Common Thrombocytopenia Uncommon Common Common Immune system disorders Hypersensitivity, allergic oedema and Anaphylaxis Uncommon Uncommon Common‡ Pruritus Uncommon Uncommon* Common Angioedema Not known Not known Not known Nervous system disorders Brain haemorrhage† Uncommon Rare Not known Eye disorders Eye haemorrhage (including conjunctival haemorrhage) Common Uncommon Not known Vascular disorders Haemorrhage, haematoma Common Common Common Hypotension (including procedural hypotension) Common Uncommon Common Intra-abdominal haemorrhage Uncommon Not known Not known Respiratory, thoracic and mediastinal disorders Epistaxis Common Common Very common Haemoptysis Uncommon Uncommon Not known Respiratory tract haemorrhage Rare Rare Not known Gastrointestinal disorders Nausea Common Common Common Gastrointestinal haemorrhage Common Common Not known Haemorrhoidal haemorrhage Uncommon Uncommon Not known Mouth haemorrhage Uncommon Common Not known System organ class Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF) Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt) in adult patients Treatment of VTE and prevention of recurrent VTE in paediatric patients from 28 days to less than 18 years of age.

Haematochezia Uncommon Uncommon Common Rectal haemorrhage, gingival bleeding Common Common Common Retroperitoneal haemorrhage Rare Not known Not known Hepatobiliary disorders Liver function test abnormal, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased Uncommon Uncommon Common Gamma-glutamyltransferase increased Common Common Not known Alanine aminotransferase increased Uncommon Common Common Skin and subcutaneous tissue disorders Skin rash Uncommon Common Common Alopecia Uncommon Uncommon Common Erythema multiforme Very rare Not known Not known Cutaneous vasculitis Not known Not known Not known Musculoskeletal and connective tissue disorders Muscle haemorrhage Rare Uncommon Not known Renal and urinary disorders Haematuria Common Common Common Anticoagulant-related nephropathy Not known Not known Not known Reproductive system and breast disorders Abnormal vaginal haemorrhage, urogenital haemorrhage Uncommon Common Very common§ General disorders and administration site conditions Application site bleeding Uncommon Uncommon Not known Investigations Occult blood positive Uncommon Uncommon Not known Injury, poisoning and procedural complications Contusion Common Common Common System organ class Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF) Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt) in adult patients Treatment of VTE and prevention of recurrent VTE in paediatric patients from 28 days to less than 18 years of age.

, haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages). ‡ Includes anaphylactic reaction, drug hypersensitivity, and hypersensitivity. § Includes heavy menstrual bleeding, intermenstrual bleeding, and vaginal haemorrhage.

The use of apixaban may be associated with an increased risk of occult or overt […]

Haemorrhage risk As with other anticoagulants, patients taking apixaban are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. 9). 1). A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of apixaban is available for adults.

However, its safety and efficacy have not been established in paediatric patients (refer to the summary of product characteristics of andexanet alfa). Transfusion of fresh frozen plasma, administration of prothrombin complex concentrates (PCCs), or recombinant factor VIIa may be considered.

However, there is no clinical experience with the use of 4-factor PCC products to reverse bleeding in paediatric and adult patients who have received apixaban. 3). 5). Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid.

5). In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with apixaban.

6% per year. 1). A clinical study enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban or VKA) for 6 months.

1). 04% per year). In study CV185325, no clinically important bleeding events were reported in the 12 paediatric patients treated with apixaban and ASA ≤ 165 mg daily concomitantly. 5). Patients with prosthetic heart valves Safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation.

Therefore, the use of apixaban is not recommended in this setting. Apixaban has not been studied in paediatric patients with prosthetic heart valves; therefore, the use of apixaban is not recommended. Patients with antiphospholipid syndrome Direct acting Oral Anticoagulants (DOACs) including apixaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome.

In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2- glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Surgery and invasive procedures Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. This includes interventions for which the probability of clinically significant bleeding cannot be excluded or for which the risk of bleeding would be unacceptable.

Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. This includes interventions for which any bleeding that occurs is expected to be minimal, non-critical in its location or easily controlled.

If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. 2). 5).

Temporary discontinuation Discontinuing anticoagulants, including apixaban, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be […]

1. - Active clinically significant bleeding. 2). - Lesion or condition if considered a significant risk factor for 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.

5).