Innoklod 2,5 mg and 5 mg Film-coated tablets

Prevention of VTE: elective hip or knee replacement surgery: INNOKLOD is indicated for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.

Prevention of stroke and systemic embolism: nonvalvular atrial fibrillation (NVAF) INNOKLOD is also indicated to reduce the risk of stroke, systemic embolism, and death in patients with nonvalvular atrial fibrillation with one or more risk factors.

Treatment of VTE INNOKLOD is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE.

If a dose is missed, the patient should take INNOKLOD immediately and then continue with twice daily administration as before.

Posology Recommended dosage.

Prevention of VTE: elective hip or knee replacement surgery The recommended dose of INNOKLOD is 2,5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery. In patients undergoing hip replacement surgery, the recommended duration of treatment is 32 to 38 days. In patients undergoing knee replacement surgery, the recommended duration of treatment is 10 to 14 days.

Prevention of stroke and systemic embolism: NVAF The recommended dose of INNOKLOD is 5 mg taken orally twice daily. Age, body weight, serum creatinine In patients with at least 2 of the following characteristics, age u2265 80 years, body weight u2264 60 kg, or serum creatinine u2265 1,5 mg/dL (133 micromole/L), the recommended dose of INNOKLOD is 2,5 mg twice daily.

Treatment of DVT and PE The recommended dose of INNOKLOD is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.

Prevention of recurrent DVT and PE The recommended dose of INNOKLOD is 2,5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.

Converting from or to parenteral anticoagulants In general, switching treatment from parenteral anticoagulants to INNOKLOD (and vice versa) can be done at the next scheduled dose.

Converting from or to warfarin or other vitamin K antagonists (VKA) When converting patients from warfarin or other VKA therapy to INNOKLOD, discontinue warfarin or other VKA therapy and start INNOKLOD when the international normalised ratio (INR) is below 2,0.

When converting from INNOKLOD to warfarin or other VKA therapy, continue INNOKLOD for 48 hours after the first dose of warfarin or other VKA therapy.

Patients undergoing cardioversion INNOKLOD can be initiated or continued in NVAF patients who may require cardioversion. For patients not previously treated with anticoagulants, at least 5 doses of INNOKLOD 5 mg twice daily (2,5 mg twice daily in patients who qualify for a dose reduction) should be given before cardioversion to ensure adequate anticoagulation. If cardioversion is required before 5 doses of INNOKLOD can be administered, a 10 mg loading dose should be given, followed by 5 mg twice daily. The dosing regimen should be reduced to a 5 mg loading dose followed by 2,5 mg twice daily if the patient meets the criteria for dose reduction. The administration of the loading dose should be given at least 2 hours before cardioversion. Confirmation should be sought prior to cardioversion that the patient has taken INNOKLOD as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.

Special populations Body weight Prevention of VTE: elective hip or knee replacement surgery No dose adjustment required (see section 5.2). Prevention of stroke and systemic embolism: NVAF See section 4.2, Prevention of stroke and systemic embolism: NVAF, Recommended dosage, Age, body weight, serum creatinine. Treatment of VTE No dose adjustment required (see section 5.2). Renal impairment: Prevention of VTE: elective hip or knee replacement surgery In surgical patients no dose adjustment is necessary in patients with mild, moderate or severe (creatinine clearance 15 - 29 mL/min) renal impairment (see section 5.2). Because there is limited clinical experience in patients with creatinine clearance < 15 mL/min and there are no data in patients undergoing dialysis, INNOKLOD is not recommended in these patients (see section 4.4, Renal impairment, Prevention of VTE: elective hip or knee replacement surgery and section 5.2).

• Hypersensitivity to the active substance (apixaban) or to any of the excipients of INNOKLOD (listed in section 6.1)
• Clinically significant active bleeding
• INNOKLOD is not recommended in patients with severe renal disease (CrCl < 15 mL/min)
• INNOKLOD is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk
• INNOKLOD should not be administered with antiplatelet medicines other than aspirin (see section 4.4)
• Patients with antiphospholipid syndrome (APS) with persistent positivity for all three antiphospholipid antibodies (patients with triple positive APS)
• 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.

Haemorrhage risk Patients taking INNOKLOD are to be carefully observed for signs of bleeding. INNOKLOD is recommended to be used with caution in conditions with increased risk of haemorrhage, such as: congenital or acquired bleeding disorders; active ulcerative gastrointestinal disease; bacterial endocarditis; thrombocytopenia; platelet disorders; history of haemorrhagic stroke; severe uncontrolled hypertension; and recent brain, spinal, or ophthalmological surgery. INNOKLOD administration should be discontinued if severe haemorrhage occurs (see section 4.9). In the event of haemorrhagic complications, treatment must be discontinued, and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical haemostasis or the transfusion of fresh frozen plasma, should be considered. If life-threatening bleeding cannot be controlled by the above measures, administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered. Reversal of INNOKLOD pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, has been demonstrated after administration of 4-factor PCCs in healthy subjects. However, there is no clinical experience with the use of 4-factor PCC medicines to reverse bleeding in individuals who have received INNOKLOD. Currently there is no experience with the use of recombinant factor VIIa in individuals receiving INNOKLOD. Standard anticoagulation tests cannot be used to monitor INNOKLOD (see section 4.5).

Interaction with other medicines affecting haemostasis The concomitant use of INNOKLOD with antiplatelet medicines increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. Other platelet aggregation inhibitors or other antithrombotic medicines are not recommended concomitantly with INNOKLOD following surgery (see section 4.5).

In patients with atrial fibrillation and a condition that warrants chronic use of aspirin, INNOKLOD may be used with due regard to increased risk of major bleeding. In a clinical trial of patients with atrial fibrillation, concomitant use of aspirin increased the major bleeding risk on INNOKLOD from 1,8 % per year to 3,4 % per year and increased the bleeding risk on warfarin from 2,7 % per year to 4,6 % per year.

Use of thrombolytic agents for the treatment of acute ischemic stroke There is very limited experience with the use of thrombolytic agents for the treatment of acute ischemic stroke in patients administered apixaban (see section 4.5).

Patients with prosthetic heart valves Safety and efficacy of INNOKLOD have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of INNOKLOD is not recommended in this setting.

Patients with antiphospholipid syndrome Treatment of patients with established APS is not recommended as evidence regarding safety and efficacy, including the benefit/harm balance of INNOKLOD in patients with APS, is inconclusive/incomplete. There is some evidence that treatment with INNOKLOD may be associated with an increased risk of recurrent arterial thrombotic events in patients with APS compared to treatment of these patients with warfarin, a vitamin K antagonist.

Surgery and invasive procedures INNOKLOD should be discontinued 2 to 3 days prior to elective surgery or invasive procedures such as neuraxial regional anaesthesia. If surgery or invasive procedures cannot be delayed, exercise appropriate caution taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.

Temporary discontinuation of INNOKLOD Discontinue INNOKLOD, in the presence of active bleeding, elective surgery, or invasive procedures that place patients at an increased risk of haemorrhage. Restart INNOKLOD therapy 12 - 24 hours after the danger of haemorrhage has ceased.

Spinal/epidural anaesthesia or puncture When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic medicines, such as INNOKLOD, for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicines affecting haemostasis. When an indwelling epidural or intrathecal catheter procedure is planned, INNOKLOD should be stopped 48 hours beforehand. Indwelling epidural or intrathecal catheters must be removed at least 6 hours prior to the first dose of INNOKLOD. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention, the medical practitioner should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.

Acute PE in haemodynamically unstable patients or patients who require thrombolysis or pulmonary embolectomy Treatment of VTE Initiation of INNOKLOD is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with haemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Patients with active cancer Patients with active cancer can be at high risk of both venous thromboembolism and bleeding events. When apixaban is considered for DVT or PE treatment in cancer patients, a careful assessment of the benefits against the risks should be made.

Interaction with strong inhibitors of both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) INNOKLOD can be administered with caution in patients receiving concomitant systemic treatment with strong inhibitors of both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g., ritonavir). These medicines may increase INNOKLOD exposure by 2-fold (see section 4.5).

Interaction with strong inducers of both CYP3A4 and P-gp The concomitant use of INNOKLOD with strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital (phenobarbitone) or St. Johnu2019s Wort) may lead to a ~50 % reduction in INNOKLOD exposure. Use caution when co-administering INNOKLOD with strong inducers of both CYP3A4 and P-gp (see section 4.5).

Effect of other medicines on INNOKLOD Inhibitors of CYP3A4 and P-gp Co-administration of INNOKLOD with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean INNOKLOD AUC and a 1,6-fold increase in mean INNOKLOD C max (see section 4.4, Interaction with inhibitors of both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp)). The dose of INNOKLOD must not exceed 2,5 mg twice daily when used with these medicines.

Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp (e.g., diltiazem, naproxen, clarithromycin, amiodarone, verapamil, quinidine) are expected to increase INNOKLOD plasma concentration to a lesser extent. No dose adjustment for INNOKLOD is required when co-administered with medicines that are not strong inhibitors of both CYP3A4 and P-gp. Diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1,4-fold increase in mean INNOKLOD AUC and a 1,3-fold increase in C max. Naproxen (500 mg, single dose), an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1,5-fold and 1,6-fold increase in mean INNOKLOD AUC and C max, respectively. Clarithromycin (500 mg, twice a day), an inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1,6-fold and 1,3-fold increase in mean INNOKLOD AUC and C max respectively.

Inducers of CYP3A4 and P-gp Co-administration of INNOKLOD with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54 % and 42 % decrease in mean INNOKLOD AUC and C max, respectively. The concomitant use of INNOKLOD with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital (phenobarbitone) or St. Johnu2019s Wort) may also lead to reduced INNOKLOD plasma concentrations. No dose adjustment for INNOKLOD is required during concomitant therapy with such medicines, however strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see section 4.4, Interaction with strong inducers of both CYP3A4 and P-gp).

For the treatment of DVT and PE, concomitant therapy with strong inducers of both CYP3A4 and P-gp is not recommended (see section 4.4). For the prevention of recurrent DVT and PE, strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see section 4.4).

Anticoagulants, platelet aggregation inhibitors, and NSAIDs After combined administration of enoxaparin (40 mg single dose) with INNOKLOD (5 mg single dose), an additive effect on anti-FXa activity was observed. Pharmacokinetic or pharmacodynamic interactions were not evident in healthy subjects when INNOKLOD was co-administered with aspirin 325 mg once a day. INNOKLOD co-administered with clopidogrel (75 mg once daily) or with the combination of clopidogrel 75 mg and aspirin 162 mg once daily or with prasugrel (60 mg followed by 10 mg once daily) in Phase 1 studies did not show a relevant increase in bleeding time or further inhibition of platelet aggregation compared to administration of the antiplatelet medicines without INNOKLOD. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of INNOKLOD alone. However, the co-administration of INNOKLOD with clopidogrel, ticagrelor or other antiplatelet medicines, except aspirin, are not recommended due to the resulting associated increased risk of major bleeds (see section 4.3). Naproxen (500 mg), an inhibitor of P-gp, led to a 1,5-fold and 1,6-fold increase in mean INNOKLOD AUC and C max, in healthy subjects, respectively. Corresponding increases in clotting tests were observed for INNOKLOD. No clinically relevant prolongation of bleeding time was observed after concomitant administration of INNOKLOD and naproxen. INNOKLOD should be used with caution when co-administered with NSAIDs (including aspirin) because these medicines typically increase the bleeding risk. Medicines associated with serious bleeding are not recommended concomitantly with INNOKLOD, such as: unfractionated heparins and heparin derivatives (including low molecular weight heparins (LMWH)), FXa inhibiting oligosaccharides (e.g. fondaparinux), direct thrombin II inhibitors (e.g., desirudin), thrombolytic medicines, GPIIb/IIIa receptor antagonists, dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists, and other oral anticoagulants. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter (see section 4.4, Interaction with other medicines affecting haemostasis).

Other concomitant therapies No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when INNOKLOD was co-administered with atenolol or famotidine. The administration of INNOKLOD 10 mg with famotidine 40 mg had no effect on INNOKLOD AUC or Cmax.

Effect of INNOKLOD on other medicines In vitro INNOKLOD studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 > 45 u03bcM) and weak inhibitory effect on the activity of CYP2C19 (IC50 > 20 u03bcM) at concentrations that are significantly greater than peak plasma concentrations observed in patients. INNOKLOD did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 u03bcM. Therefore, INNOKLOD is not expected to alter the metabolic clearance of co-administered medicines that are metabolised by these enzymes. INNOKLOD is not a significant inhibitor of P-gp. INNOKLOD did not meaningfully alter the pharmacokinetics of digoxin, naproxen, or atenolol.

Safety has not been established.

Pregnancy INNOKLOD is not recommended during pregnancy. Treatment may increase the risk of haemorrhage during pregnancy and delivery.

Breastfeeding. It is unknown whether INNOKLOD or its metabolites are excreted in human milk. In rat milk, a high milk to maternal plasma ratio (C max about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to newborns and infants cannot be excluded. Women taking INNOKLOD should not breastfeed their infants.

INNOKLOD has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile The most frequent side effects with INNOKLOD are haemorrhage, contusion, epistaxis, and haematoma.

Tabulated summary of adverse reactions

Table 1: Tabulated adverse reactions.

System organ class Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp) 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)

Blood and lymphatic system disorders Anaemia Frequent Frequent Frequent Thrombocytopenia Less frequent Less frequent Frequent Immune system disorders Hypersensitivity, allergic oedema and anaphylaxis Less frequent Less frequent Less frequent Pruritus Less frequent Less frequent Less frequent Angioedema Frequency unknown Frequency unknown Frequency unknown Nervous System disorders Brain haemorrhage u2020 Frequency unknown Less frequent Less frequent Eye Disorders Eye Haemorrhage (including conjunctival haemorrhage) Less frequent Frequent Frequency unknown Vascular disorders Haemorrhage, haematoma Frequent Frequent Frequent Hypotension (including procedural hypotension) Less frequent Frequent Less frequent Intra-abdominal haemorrhage Frequency unknown Less frequent Frequency unknown Respiratory, thoracic and mediastinal disorders Epistaxis Less Frequent Frequent Frequent Haemoptysis Less frequent Less frequent Less frequent Respiratory tract haemorrhage Frequency unknown Less frequent Less frequent Gastrointestinal disorders Nausea Frequent Frequent Frequent Gastrointestinal haemorrhage Less frequent Frequent Frequent Haemorrhoidal haemorrhage Frequency unknown Less frequent Less frequent Mouth haemorrhage Frequency unknown Less frequent Frequent Haematochezia Less frequent Less frequent Less frequent Rectal haemorrhage, gingival bleeding Less frequent Frequent Frequent Retroperitoneal haemorrhage Frequency unknown Less frequent Frequency unknown Hepatobiliary disorders Liver function test abnormal, increased asparate aminotransferase, increased blood alkaline phosphatase, increased blood bilirubin Less frequent Less frequent Less frequent Increased gamma-glutamyltransferase Less frequent Frequent Frequent Increased alanine aminotransferase Less frequent Less frequent Frequent Skin and subcutaneous tissue disorders Skin rash Frequency unknown Less frequent Frequent Alopecia Less frequent Less frequent Less frequent Musculoskeletal and connective tissue disorders Muscle haemorrhage Less frequent Less frequent Less frequent Renal and urinary disorders Haematuria Less frequent Frequent Frequent Reproductive system and breast disorders Abnormal vaginal haemorrhage, urogenital haemorrhage Less frequent Less frequent Frequent General disorders and administration site conditions Application site bleeding Frequency unknown Less frequent Less frequent Investigations Positive occult blood Frequency unknown Less frequent Less frequent Injury, poisoning and procedural complications Contusion Frequent Frequent Frequent Post procedural haemorrhage Less frequent Less frequent Less frequent (including post procedural haematoma, wound haemorrhage, vessel puncture site haematoma and catheter site haemorrhage), wound secretion, incision site haemorrhage (including incision site haematoma), operative haemorrhage Traumatic haemorrhage Frequent unknown Less frequent Less frequent

u2020 The term u201cBrain haemorrhageu201d encompasses all intracranial or intraspinal haemorrhages (i.e., haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8 HOTLINE for reporting of side effects directly to Innovata Pharmaceuticals (Pty) Ltd: 086 999 0912.

There is no antidote to INNOKLOD. Overdose of INNOKLOD may result in a higher risk of bleeding. Administration of activated charcoal may be useful in the management of INNOKLOD overdose or accidental ingestion. Haemodialysis is unlikely to be an effective means of managing INNOKLOD overdose. Treatment should be symptomatic and supportive.