Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
CLEAN PROFESSIONAL INFORMATION FOR RIVAHET 10, 15 & 20  
SCHEDULING STATUS  
S4  
WARNING: (A) PREMATURE DISCONTINUATION OF RIVAHET INCREASES THE RISK OF  
THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HAEMATOMA  
A. Premature discontinuation of RIVAHET increases the risk of thrombotic events:  
Premature discontinuation of any oral anticoagulant, including RIVAHET, increases the  
risk of thrombotic events. If anticoagulation with RIVAHET is discontinued for a reason  
other than pathological bleeding or completion of a course of therapy, consider coverage  
with another anticoagulant (see sections 4.2 and 4.4.).  
B. Spinal/epidural haematoma:  
Epidural or spinal hematomas have occurred in patients treated with RIVAHET who are  
receiving neuraxial anaesthesia or undergoing spinal puncture. These haematomas may  
result in long-term or permanent paralysis.  
Consider these risks when scheduling patients for spinal procedures.  
Factors that can increase the risk of developing epidural or spinal haematomas in these  
patients include:  
•
•
Use of indwelling epidural catheters.  
Concomitant use of other medicines that affect haemostasis, such as  
nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other  
anticoagulants.  
•
•
•
History of traumatic or repeated epidural or spinal punctures.  
History of spinal deformity or spinal surgery.  
Optimal timing between the administration of RIVAHET and neuraxial procedures  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
is not known (see sections 4.4 and 4.8).  
Monitor patients frequently for signs and symptoms of neurological impairment. If  
neurological compromise is noted, urgent treatment is necessary (see section 4.4).  
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or  
to be anticoagulated for thromboprophylaxis (see section 4.4).  
1 NAME OF THE MEDICINE  
RIVAHET 10 film coated tablets  
RIVAHET 15 film coated tablets  
RIVAHET 20 film coated tablets  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
RIVAHET 10: Each film coated tablet contains 10 mg rivaroxaban.  
RIVAHET 15: Each film coated tablet contains 15 mg rivaroxaban.  
RIVAHET 20: Each film coated tablet contains 20 mg rivaroxaban.  
Contains sugar (lactose monohydrate).  
RIVAHET 10: Contains 76,200 mg lactose monohydrate per tablet.  
RIVAHET 15: Contains 17.175 mg lactose monohydrate per tablet.  
RIVAHET 20: Contains 22,900 mg lactose monohydrate per tablet.  
For a full list of excipients, see section 6.1.  
3 PHARMACEUTICAL FORM  
RIVAHET 10: Orange, film coated, round shaped biconvex tablets, debossed with “R21” on one  
side and “H” on the other side.  
RIVAHET 15: Grey, film coated, round shaped biconvex tablets, debossed with “R22” on one side  
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Page 2 of 37  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
and “H” on the other side.  
RIVAHET 20: Light grey, film coated, round shaped biconvex tablets, debossed with “R23” on one  
side and “H” on the other side.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
RIVAHET 10 is indicated for the prevention of venous thromboembolism (VTE) in patients  
undergoing major orthopaedic surgery of the lower limbs.  
RIVAHET 15 and RIVAHET 20 are indicated for:  
•
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial  
fibrillation (SPAF) with one or more risk factors, such as congestive heart failure,  
hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack.  
Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein  
thrombosis (DVT) and pulmonary embolism (PE).  
•
•
Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary  
embolism (PE) and deep vein thrombosis (DVT).  
4.2 Posology and method of administration  
Posology  
Recommended dose and frequency of administration for RIVAHET 10:  
The recommended dose is one RIVAHET 10 tablet once daily for the prevention of venous  
thromboembolism (VTE) in major orthopaedic surgery.  
The initial dose should be taken within 6 - 10 hours after surgery provided that haemostasis has  
been established.  
If a dose is missed the patient should take RIVAHET 10 immediately and continue on the following  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
day with the once daily intake as before.  
Duration of treatment:  
The duration of treatment depends on the type of major orthopaedic surgery.  
After major hip surgery patients should be treated for 5 weeks.  
After major knee surgery patients should be treated for 2 weeks.  
Special populations  
Elderly (above 65 years), gender and body weight:  
No dose adjustment is required for these patient populations.  
Patients with impaired liver function:  
RIVAHET 10 is contra-indicated in patients with significant hepatic disease which is associated with  
coagulopathy leading to a clinically relevant bleeding risk. (see section 4.3).  
No dose adjustment is necessary in patients with other hepatic diseases.  
Limited clinical data in patients with moderate hepatic impairment indicate a significant increase in  
the pharmacological activity. No clinical data are available for patients with severe hepatic  
impairment.  
Patients with impaired renal function:  
No dose adjustment is required if RIVAHET 10 is administered in patients with mild (creatinine  
clearance 80 – 50 mL/min) or moderate (creatinine clearance < 50 – 30 mL/min) renal impairment.  
Limited clinical data for patients with severe renal impairment (creatinine clearance < 30 mL/min)  
indicate that rivaroxaban plasma levels are significantly increased in this patient population.  
Therefore RIVAHET 10 must be used with caution in these patients (see section 4.4).  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
Ethnic differences:  
No dose adjustment is required based on ethnic differences.  
Paediatric population  
The safety and efficacy of RIVAHET 10 has not been established in children. No clinical data is  
available for children.  
Recommended dose and frequency of administration for RIVAHET 15 and RIVAHET 20:  
SPAF – Recommended usual dose and frequency of administration:  
The recommended dose is one RIVAHET 20 tablet once daily.  
For patients with moderate renal impairment (creatinine clearance < 50 to 30 mL/min) the  
recommended dose is one RIVAHET 15 tablet once daily.  
SPAF – Duration of treatment:  
Therapy should be continued as long as risk factors for stroke and systemic embolism persist.  
SPAF – Missed dose:  
If a dose is missed the patient should take RIVAHET 15 or RIVAHET 20 immediately and continue  
with the once daily intake as recommended on the following day.  
The dose should not be doubled to make up for a missed dose within the same day.  
SPAF – Maximum daily dose:  
The recommended maximum daily dose is one RIVAHET 20 tablet (20 mg rivaroxaban).  
DVT and PE treatment – Recommended usual dose and frequency of administration:  
The recommended dose for the initial treatment of acute DVT and PE is one RIVAHET 15 tablet  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
twice daily for the first three weeks followed by one RIVAHET 20 tablet once daily for the continued  
treatment and the prevention of recurrent DVT and PE.  
DVT and PE treatment – Duration of treatment:  
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 rivaroxaban 10 mg once  
daily, a dose of rivaroxaban 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 4.4).  
The duration of therapy and dose selection should be individualised after careful assessment of the  
treatment benefit against the risk for bleeding (see section 4.4).  
Time period  
Day 1 - 21  
Dosing schedule  
15 mg twice daily  
20 mg once daily  
Total daily dose  
30 mg  
Treatment  
prevention  
and  
of  
Day 22 onwards  
20 mg  
recurrent DVT and  
PE  
Prevention  
of  
Following  
10 mg once daily or  
20 mg once daily  
10 mg or 20 mg  
recurrent DVT and  
PE  
completion  
least  
of  
at  
6
months  
therapy for DVT or  
PE  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
DVT and PE treatment – Missed dose:  
It is essential to adhere to the dosage schedule provided.  
If a dose is missed during the RIVAHET 15 twice daily treatment phase (day 1 to 21) the patient  
should take RIVAHET 15 immediately to ensure intake of 30 mg RIVAHET per day. In this case  
two 15 mg tablets may be taken at once. The patient should continue with the regular one  
RIVAHET 15 tablet twice daily intake as recommended on the following day.  
If a dose is missed during the once daily treatment phase, the patient should take RIVAHET  
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.  
DVT and PE treatment – Maximum daily dose:  
The recommended maximum daily dose is 30 mg during the first 3 weeks of treatment.  
In the following treatment phase the recommended maximum daily dose is 20 mg.  
Converting from warfarin to RIVAHET 15 or RIVAHET 20:  
Warfarin treatment should be stopped and RIVAHET 15 or RIVAHET 20 therapy should be initiated  
once the INR is ≤ 3,0.  
For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped  
and RIVAHET therapy should be initiated once the INR is ≤ 2,5.  
When converting patients from warfarin to RIVAHET 15 or RIVAHET 20, INR values will be falsely  
elevated after the intake of RIVAHET 15 or RIVAHET 20. The INR is not valid to measure the  
anticoagulant activity of RIVAHET 15 or RIVAHET 20, and therefore should not be used (see  
section 4.5).  
Converting from RIVAHET 15 and RIVAHET 20 to warfarin:  
There is a potential for inadequate anticoagulation during the transition from RIVAHET 15 and  
RIVAHET 20 to warfarin. Continuous adequate anticoagulation should be ensured during any  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
transition to an alternate anticoagulant. It should be noted that RIVAHET 15 and RIVAHET 20 can  
contribute to an elevated INR.  
In patients converting from RIVAHET 15 or RIVAHET 20 to warfarin, warfarin should be given  
concurrently until the INR is ≥ 2,0. For the first two days of the conversion period, standard warfarin  
dosing should be used followed by warfarin dosing guided by INR testing. While patients are on  
both RIVAHET 15 or RIVAHET 20 and warfarin, the INR should not be tested earlier than 24 hours  
(after the previous dose but prior to the next dose of RIVAHET 15 or RIVAHET 20). Once  
RIVAHET 15 or RIVAHET 20 is discontinued, INR testing may be done reliably 24 hours after the  
last dose (see section 4.5).  
Converting from parenteral anticoagulants to RIVAHET 15 or RIVAHET 20:  
For patients currently receiving a parenteral anticoagulant, start RIVAHET 15 or RIVAHET 20, 0 to  
2 hours before the time of the next scheduled administration of the parenteral medicine (e.g.  
LMWH) or at the time of discontinuation of a continuously administered parenteral medicine (e.g.  
intravenous unfractionated heparin).  
Converting from RIVAHET 15 or RIVAHET 20 to parenteral anticoagulants:  
Discontinue RIVAHET 15 or RIVAHET 20 and give the first dose of parenteral anticoagulant at the  
time that the next RIVAHET 15 or RIVAHET 20 dose would have been taken.  
There is no need for monitoring of coagulation parameters during treatment with RIVAHET 15 and  
RIVAHET 20.  
Special populations  
Patients with hepatic impairment:  
RIVAHET 15 and RIVAHET 20 are contraindicated in patients with hepatic disease with  
coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and  
C (see section 4.3).  
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Page 8 of 37  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
Limited data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant  
increase in the pharmacological activity.  
No data is available for patients with severe hepatic impairment (Child Pugh C) (see sections 4.3  
and 5.2).  
Patients with renal impairment:  
No dose adjustment is required if RIVAHET 15 and RIVAHET 20 is administered in patients with  
mild (creatinine clearance ≤ 80 to 50 mL/min) renal impairment. For patients with moderate  
(creatinine clearance <50 to 30 mL/min) renal impairment the recommended dose is one RIVAHET  
15 once daily.  
Limited data for patients with severe renal impairment (creatinine clearance < 30 to 15 mL/min)  
indicate that rivaroxaban plasma levels are significantly increased in this patient population.  
Therefore RIVAHET 15 and RIVAHET 20 must be used with caution in these patients. Use of  
RIVAHET 15 and RIVAHET 20 are not recommended in patients with creatinine clearance < 15  
mL/min (see sections 4.4 and 5.2).  
In patients with moderate (creatinine clearance 30 - 49 mL/min) or severe (creatinine clearance 15  
- 29 mL/min) renal impairment the following dose 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 5.2).  
•
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 4.4,  
5.1 and 5.2). When the recommended dose is 10 mg once daily, no dose adjustment from  
the recommended dose is necessary.  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
Body weight:  
No dose adjustment is required based on body weight (see section 5.2).  
Patients undergoing cardioversion  
RIVAHET can be initiated or continued in patients who may require cardioversion. For  
transoesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated  
with anticoagulants, RIVAHET treatment should be started at least 4 hours before cardioversion to  
ensure adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should  
be sought prior to cardioversion that the patient has taken RIVAHET as prescribed. Decisions on  
initiation and duration of treatment should take established guideline recommendations for  
anticoagulant treatment in patients undergoing cardioversion into account.  
Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary  
intervention) with stent placement  
There is limited experience of a reduced dose of 15 mg rivaroxaban once daily (or 10 mg  
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  
sections 4.4 and 5.1).  
Paediatric population  
Children and adolescents (from birth to 18 years):  
Safety and efficacy have not been established in children and adolescents below 18 years.  
Method of administration  
RIVAHET should be taken orally with or without food.  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
4.3 Contraindications  
•
Known hypersensitivity to rivaroxaban or to any of the excipients of RIVAHET (see section  
6.1).  
•
•
•
Clinically significant active bleeding (e.g. intracranial bleeding, gastrointestinal bleeding).  
Known existing inherited bleeding disorders.  
Significant hepatic disease which is associated with coagulopathy leading to a clinically  
relevant bleeding risk including cirrhotic patients with Child Pugh B and C.  
Lesion or condition, if considered to be a significant risk 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.  
•
•
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH),  
low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives  
(fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.)  
except under specific circumstances of switching anticoagulant therapy (see section 4.2) or  
when UFH is given at doses necessary to maintain an open central venous or arterial  
catheter (see section 4.5).  
•
•
Concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a  
transient ischaemic attack (TIA) (see section 4.4).  
Concomitant treatment of CAD/PAD with aspirin in patients with previous haemorrhagic or  
lacunar stroke, or any stroke within a month (see section 4.4).  
•
•
•
Pregnancy and lactation (see section 4.6).  
Persistent triple positive antiphospholipid syndrome (APS).  
Renally impaired patients with creatinine clearance < 15 mL/min.  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
4.4 Special warnings and precautions for use  
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment  
period.  
Haemorrhagic risk:  
Patients taking rivaroxaban as in RIVAHET are to be carefully observed for signs of bleeding. It is  
recommended to be used with caution in conditions with increased risk of haemorrhage. RIVAHET  
administration should be discontinued if severe haemorrhage occurs.  
In clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary  
including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more  
frequently during long term rivaroxaban treatment. Thus, in addition to adequate clinical  
surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult  
bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate.  
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients  
are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after  
initiation of treatment (see section 4.8).  
In patients receiving RIVAHET 10 for VTE prevention following elective hip or knee replacement  
surgery, this may be done by regular physical examination of the patients, close observation of the  
surgical wound drainage and periodic measurements of haemoglobin.  
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.  
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban  
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional  
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g.  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
overdose and emergency surgery (see sections 5.1 and 5.2).  
Other haemorrhagic risk factors:  
Rivaroxaban should be used with caution in patients with an increased bleeding risk such as:  
•
•
•
•
•
Congenital or acquired bleeding disorders  
Uncontrolled severe arterial hypertension  
Active ulcerative gastrointestinal disease  
Recent gastrointestinal ulcerations  
Other gastrointestinal disease without active ulceration that can potentially lead to bleeding  
complications  
(e.g.  
inflammatory  
bowel  
disease,  
oesophagitis,  
gastritis  
and  
gastroesophageal reflux disease)  
Vascular retinopathy  
•
•
•
•
Recent intracranial or intracerebral haemorrhage  
Shortly after brain, spinal or ophthalmological surgery  
Bronchiectasis or history of pulmonary bleeding (haemoptysis)  
Renal impairment:  
In patients with severe renal impairment (creatinine clearance < 30 mL/min) rivaroxaban plasma  
levels may be significantly elevated which may lead to an increased bleeding risk. Due to the  
underlying disease these patients are at an increased risk of both bleeding and thrombosis.  
Therefore, due to limited clinical data RIVAHET should be used with caution in patients with severe  
renal impairment.  
RIVAHET is to be used with caution in patients with creatinine clearance 15 - 29 mL/min. Use is  
contraindicated in patients with creatinine clearance < 15 mL/min (see sections 4.2 and 5.2).  
In patients with moderate renal impairment (creatinine clearance 30 to 49 mL/min) concomitantly  
receiving other medicines which increase rivaroxaban plasma concentrations, RIVAHET is to be  
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Page 13 of 37  
Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
used with caution (see section 4.5). Patients with severe renal impairment or increased bleeding  
risk and patients receiving concomitant systemic treatment with azole-antimycotics or HIV protease  
inhibitors are to be carefully monitored for signs of bleeding complications after initiation of  
treatment.  
Interaction with other medicines:  
The use of RIVAHET is not recommended in patients receiving concomitant systemic treatment  
with azole-antimycotics (e.g. ketoconazole) or HIV protease inhibitors (e.g. ritonavir). These  
medicines are strong inhibitors of both CYP3A4 and P-gp. Therefore, these medicines may  
increase rivaroxaban plasma concentrations to a clinically relevant degree which may lead to an  
increased bleeding risk (see section 4.5). The azole anti-mycotic fluconazole, a moderate CYP 3A4  
inhibitor, has however less effect on rivaroxaban exposure and can be co-administered (see  
section 4.5).  
After treatment is initiated, patients should be carefully monitored for signs of bleeding  
complications. This may be done by regular physical examination of the patients, close observation  
of the surgical wound drainage and periodic measurements of haemoglobin.  
Care should be taken if patients are treated concomitantly with medicines affecting haemostasis  
such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or selective  
serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), or  
other antithrombotics (see section 4.5). For patients at risk of ulcerative gastrointestinal disease an  
appropriate prophylactic treatment may be considered.  
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.  
RIVAHET should be used in women of childbearing potential only with effective contraception.  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
No QTc prolonging effect was observed with rivaroxaban, as in RIVAHET.  
Neuraxial (epidural/spinal) anaesthesia:  
When neuraxial (epidural/ spinal) anaesthesia or spinal puncture is performed patients treated with  
antithrombotics for prevention of thromboembolic complications are at risk for development of an  
epidural or spinal haematoma which may result in long-term paralysis.  
The risk of these events is even increased by use of indwelling epidural catheters or the  
concomitant use of medicines affecting haemostasis. The risk may also be increased by traumatic  
or repeated epidural or spinal puncture.  
Patients should be frequently monitored for signs and symptoms of neurological impairment (e.g.,  
numbness or weakness of the legs, bowel or bladder dysfunction). If neurological deficits are  
noted, urgent diagnosis and treatment is necessary.  
The medical practitioner should consider the potential benefit versus the risk before neuraxial  
intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. There is no  
clinical experience with the use of 15 mg and 20 mg rivaroxaban in these situations.  
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and  
neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of  
rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed  
when the anticoagulant effect of rivaroxaban is estimated to be low (see section 5.2).  
However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not  
known.  
For the removal of an epidural catheter and based on general PK characteristics at least 2 half-  
lives, i.e., at least 18 hours in young adult patients and 26 hours in elderly patients should elapse  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
after the last administration of RIVAHET.  
The next dose of RIVAHET should be administered at earliest 6 hours after the removal of the  
catheter.  
If traumatic puncture occurs the administration of RIVAHET should be delayed for 24 hours.  
Patients with prosthetic valves:  
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone  
transcatheter aortic valve replacement (TAVR). Safety and efficacy of RIVAHET have not been  
studied in patients with prosthetic heart valves; therefore, there are no data to support that  
RIVAHET provides adequate anticoagulation in this patient population. Treatment with RIVAHET is  
not recommended for these patients.  
Patients with antiphospholipid syndrome:  
Direct acting Oral Anticoagulants (DOACs) including rivaroxaban 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.  
Patients with non-valvular atrial fibrillation who undergo PCI with stent placement:  
Clinical data are available from an interventional study with the primary objective to assess safety  
in patients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on  
efficacy in this population are limited (see sections 4.2 and 5.1). No data are available for such  
patients with a history of stroke/TIA.  
Hip fracture surgery:  
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Rivaroxaban has not been studied in interventional clinical studies in patients undergoing hip  
fracture surgery to evaluate efficacy and safety.  
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary  
embolectomy:  
RIVAHET is not recommended as an alternative to unfractionated heparin in patients with  
pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or  
pulmonary embolectomy since the safety and efficacy of RIVAHET have not been established in  
these clinical situations.  
Dosing recommendations before and after invasive procedures and surgical intervention:  
If an invasive procedure or surgical intervention is required, RIVAHET should be stopped at least  
24 hours before the intervention, if possible and based on the clinical judgement of the medical  
practitioner.  
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the  
urgency of the intervention.  
RIVAHET should be restarted as soon as possible after the invasive procedure or surgical  
intervention provided the clinical situation allows and adequate haemostasis has been established  
as determined by the treating medical practitioner (see section 5.2).  
Elderly population:  
Increasing age may increase haemorrhagic risk (see section 5.2).  
Dermatological reactions:  
Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and  
DRESS syndrome, have been reported during post-marketing surveillance in association with the  
use of rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early  
in the course of therapy: the onset of the reaction occurring in the majority of cases within the first  
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weeks of treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin  
rash (e.g. spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction  
with mucosal lesions.  
Patients with cancer:  
Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis.  
The individual benefit of antithrombotic treatment should be weighed against risk for bleeding in  
patients with active cancer dependent on tumour location, antineoplastic therapy and stage of  
disease. Tumours located in the gastrointestinal or genitourinary tract have been associated with  
an increased risk of bleeding during rivaroxaban therapy. In patients with malignant neoplasms at  
high risk of bleeding, the use of rivaroxaban is contraindicated (see section 4.3).  
Lactose warning  
RIVAHET contains lactose. Patients with rare hereditary problems of galactose intolerance, total  
lactase deficiency or glucose-galactose malabsorption should not take RIVAHET.  
4.5 Interaction with other medicine and other forms of interaction  
Pharmacokinetic interactions  
Rivaroxaban is cleared mainly via cytochrome P450-mediated (CYP 3A4, CYP 2J2) hepatic  
metabolism and renal excretion of the unchanged medicine, involving the P-glycoprotein (P-gp) /  
breast cancer resistance protein (Bcrp) transporter systems (see section 5.2).  
CYP Inhibition  
Rivaroxaban does not inhibit CYP 3A4 or any other major CYP isoforms.  
CYP Induction  
Rivaroxaban does not induce CYP 3A4 or any other major CYP isoforms.  
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Effects on RIVAHET  
The concomitant use of RIVAHET with strong CYP 3A4 and P-gp inhibitors, may lead to both  
reduced hepatic and renal clearance and thus significantly increased systemic exposure.  
Co-administration of RIVAHET with the azole-antimycotic ketoconazole (400 mg once daily) a  
strong CYP 3A4 and P-gp inhibitor, led to a 2,6-fold increase in mean rivaroxaban steady state  
AUC and a 1,7-fold increase in mean rivaroxaban Cmax, with significant increases in its  
pharmacodynamic effects which may lead to an increased bleeding risk.  
Co-administration of RIVAHET with the HIV protease inhibitor ritonavir (600 mg twice daily), a  
strong CYP 3A4 and P-gp inhibitor, led to a 2,5-fold increase in mean rivaroxaban AUC and a 1,6-  
fold increase in mean rivaroxaban Cmax, with significant increases in its pharmacodynamic effects  
which may lead to an increased bleeding risk. Data on co-administration of rivaroxaban with the  
HIV protease inhibitor ritonavir (100 mg twice daily) is not available.  
Therefore, RIVAHET is not recommended in patients receiving concomitant systemic treatment  
with azole-antimycotics or HIV-protease inhibitors (see section 4.4).  
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either  
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.  
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and  
moderate P-gp inhibitor, led to a 1,5-fold increase in mean rivaroxaban AUC and a 1,4 fold  
increase in Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients  
but can be potentially significant in high-risk patients (For patients with renal impairment: see  
section 4.4).  
Erythromycin (500 mg three times daily), which inhibits CYP 3A4 and P-gp moderately, led to a  
1,3-fold increase in mean rivaroxaban steady state AUC and Cmax. This increase is within the  
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magnitude of the normal variability of AUC and Cmax and is considered as clinically not relevant.  
Medicines strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP 3A4 or  
P-gp, potentially increase rivaroxaban plasma concentrations. The expected increase is considered  
as clinically not relevant.  
Co-administration of RIVAHET with the strong CYP 3A4 and P-gp inducer rifampicin led to an  
approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its  
pharmacodynamic effects.  
The concomitant use of RIVAHET with other strong CYP 3A4 inducers (e.g., phenytoin,  
carbamazepine, phenobarbitone or St. John’s Wort) may also lead to a decreased rivaroxaban  
plasma concentration. Strong CYP 3A4 inducers should be co-administered with caution.  
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1,4-fold  
increase in mean rivaroxaban AUC and a 1,3-fold increase in mean Cmax. The interaction with  
fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-  
risk patients (For patients with renal impairment: see section 4.4).  
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban  
should be avoided.  
Pharmacodynamic interactions  
Anticoagulants  
After combined administration of enoxaparin (40 mg single dose) with RIVAHET 10 (10 mg single  
dose), an additive effect on anti-Factor Xa activity was observed without any additional effects on  
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban (see  
section 4.4). Due to the increased bleeding risk care is to be taken if patients are treated  
concomitantly with any other anticoagulants (see sections 4.3 and 4.4).  
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NSAIDs/ platelet aggregation inhibitors  
No clinically relevant prolongation of bleeding time was observed after concomitant administration  
of RIVAHET 15 and 500 mg naproxen. Nevertheless, there may be individuals with more  
pronounced pharmacodynamic response (see section 4.4).  
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a  
pharmacokinetic interaction but a relevant increase in bleeding times was observed in a subset of  
patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels  
(see section 4.4).  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when  
RIVAHET was co-administered with 500 mg acetylsalicylic acid.  
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid)  
and platelet aggregation inhibitors because these medicines typically increase the bleeding risk  
(see section 4.4).  
SSRIs/SNRIs  
The possibility may exist that patients are at increased risk of bleeding in case of concomitant use  
with SSRIs or SNRIs due to their reported effect on platelets. When concomitantly used in the  
rivaroxaban clinical programme, numerically higher rates of major or non-major clinically relevant  
bleeding were observed in all treatment groups.  
Warfarin  
Converting patients from the vitamin K antagonist warfarin (INR 2,0 to 3,0) to rivaroxaban (20 mg)  
or from rivaroxaban (20 mg) to warfarin (INR 2,0 to 3,0) increased prothrombin time/INR  
(Neoplastin®) more than additively (individual INR values up to 12 may be observed), whereas  
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effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive. If  
it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-  
factor Xa activity, PiCT, and HepTest® can be used as these tests were not affected by warfarin.  
On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa  
activity and ETP) reflected only the effect of rivaroxaban.  
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR  
measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of  
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.  
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.  
Interactions shown not to exist  
There were no mutual pharmacokinetic interactions between RIVAHET and midazolam (substrate  
of CYP 3A4), digoxin (substrate of P-glycoprotein) or atorvastatin (substrate of CYP 3A4 and P-gp).  
Co-administration of the H2 receptor antagonist ranitidine and the antacid aluminium hydroxide  
/magnesium hydroxide did not affect rivaroxaban bioavailability and pharmacokinetics.  
Interactions with laboratory parameters  
Clotting parameter tests (PT, aPTT, HepTest®) are affected as expected by the mode of action of  
RIVAHET.  
4.6 Fertility, pregnancy and lactation  
Women of childbearing potential  
RIVAHET should be used in women of childbearing potential only with effective contraception.  
Pregnancy  
No human data on the use of RIVAHET in pregnant women are available.  
In rats and rabbits RIVAHET showed pronounced maternal toxicity with placental changes related  
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to its pharmacological mode of action (e.g., haemorrhagic complications). No primary teratogenic  
potential was identified. Animal data show that rivaroxaban crosses the placental barrier.  
Therefore, use of RIVAHET is contraindicated throughout pregnancy.  
Lactation  
No human data on use of RIVAHET in nursing mothers are available. In rats, rivaroxaban is  
secreted into breast milk. Therefore, RIVAHET may only be administered after breastfeeding is  
discontinued.  
4.7 Effects on ability to drive and use machines  
RIVAHET has minor influence on the ability to drive and use machines. Adverse reactions like  
syncope and dizziness have been reported (see section 4.8). Patients experiencing these adverse  
reactions should not drive or use machines.  
4.8  
Undesirable effects  
b) Tabulated summary of adverse reactions  
System organ class  
Blood and lymphatic system  
disorders  
Frequency  
Adverse event  
Frequent  
Anaemia  
(incl.  
respective  
laboratory parameters)  
Less frequent  
Thrombocytopenia (incl. platelet  
count increased), thrombocytosis  
(incl. platelet count increased -  
observed in prevention of VTE in  
adult patients undergoing elective  
hip or knee replacement)  
Immune system disorders  
Less frequent  
Allergic dermatitis, allergic reaction,  
anaphylactic reactions including  
anaphylactic shock, angioedema  
and allergic oedema  
Nervous system disorders  
Frequent  
Dizziness, headache  
Less frequent  
Syncope  
(incl.  
loss  
of  
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consciousness),  
cerebral  
and  
intracranial  
haemorrhage  
Eye disorders  
Frequent  
Eye  
haemorrhage (incl.  
conjunctival haemorrhage)  
Tachycardia  
Cardiac disorders  
Vascular disorders  
Less frequent  
Frequent  
Postprocedural haemorrhage (incl.  
postoperative anaemia and wound  
haemorrhage), haematoma  
Hypotension (incl. blood pressure  
Less frequent  
decreased,  
procedural  
hypotension), haemorrhage (incl.  
haematoma and rare cases of  
muscle  
gastrointestinal tract haemorrhage  
(incl. gingival bleeding, rectal  
haematemesis),  
blood urine  
haemorrhage),  
haemorrhage,  
haematuria  
(incl.  
present), genital tract haemorrhage  
(incl. menorrhagia), nosebleed  
Epistaxis, haemoptysis  
Respiratory,  
thoracic  
and  
Frequent  
mediastinal disorders  
Gastrointestinal disorders  
Less frequent  
Frequent  
Eosinophilic pneumonia  
Nausea, diarrhoea, abdominal and  
gastrointestinal pain (incl. upper  
abdominal  
discomfort),  
epigastric  
pain,  
stomach  
(incl.  
dyspepsia  
discomfort),  
vomiting  
(observed in prevention of VTE in  
adult patients undergoing elective  
hip or knee replacement)  
Less frequent  
Constipation  
(observed  
in  
prevention of VTE in adult patients  
undergoing elective hip or knee  
replacement),  
Hepato-biliary disorders  
Frequent  
Increase in transaminases  
Less frequent  
Hepatic  
function  
abnormal,  
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cholestasis,  
impairment,  
jaundice,  
hepatic  
(incl.  
hepatitis  
hepatocellular injury)  
Cutaneous and  
Skin and subcutaneous tissue  
disorders  
Frequent  
subcutaneous  
haemorrhage, ecchymosis, pruritus  
(incl. rare cases of generalised  
pruritus), rash  
Less frequent  
Urticaria (incl. rare cases of  
generalised urticaria), contusion,  
Stevens-Johnson syndrome/Toxic  
Epidermal  
syndrome  
necrolysis,  
DRESS  
Musculoskeletal and connective  
tissue disorders  
Frequent  
Pain in extremity (observed in  
prevention of VTE in adult patients  
undergoing elective hip or knee  
replacement)  
Less frequent  
Frequent  
Compartment syndrome secondary  
to  
muscle haemorrhage  
Urogenital tract haemorrhage (incl.  
haematuria and menorrhagia  
a
bleeding,  
haemarthrosis,  
Renal and urinary disorders  
observed in treatment of DVT, PE  
and prevention of recurrence as  
very common in women < 55  
years), renal impairment (incl.  
blood creatinine increased, blood  
urea  
increased  
observed  
in  
prevention of VTE in adult patients  
undergoing elective hip or knee  
replacement)  
Less frequent  
Frequent  
Renal failure / acute renal failure  
secondary to a bleeding sufficient  
to cause hypoperfusion  
General  
disorders  
and  
Fever,  
peripheral  
oedema,  
administration site conditions  
decreased general strength and  
energy (incl.  
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fatigue and asthenia)  
Less frequent  
Feeling unwell (incl. malaise), fever  
(observed in prevention of VTE in  
adult patients undergoing elective  
hip or knee replacement), localised  
oedema (observed in prevention of  
VTE in adult patients undergoing  
elective hip or knee replacement  
surgery)  
Investigations  
Frequent  
Increased  
GGT,  
increase  
in  
transaminases (incl. ALT increase,  
AST increase)  
Less frequent  
Increased  
lipase,  
increased  
amylase, blood bilirubin increased,  
increased LDH, increased alkaline  
phosphatase  
(observed  
in  
prevention of VTE in adult patients  
undergoing elective hip or knee  
replacement), bilirubin conjugated  
increased  
(with  
or  
without  
concomitant increase of ALT),  
jaundice  
Injury, poisoning and procedural  
complications  
Frequent  
Post-procedural haemorrhage (incl.  
postoperative anaemia, and wound  
haemorrhage)  
Less frequent  
Wound secretion (observed in  
prevention of VTE in adult patients  
undergoing elective hip or knee  
replacement  
pseudoaneurysm - observed as  
uncommon in prevention of  
atherothrombotic events in patients  
surgery),  
vascular  
after  
an  
ACS  
(following  
coronary  
percutaneous  
intervention)  
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c. Description of selected adverse reactions  
Due to the pharmacological mode of action, the use of RIVAHET may be associated with an  
increased risk of occult or overt bleeding from any tissue or organ which may result in post  
haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary  
according to the location and degree or extent of the bleeding and/or anaemia (see section 4.9  
Management of bleeding). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival,  
gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and  
anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA  
treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of  
haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical  
relevance of overt bleeding, as judged to be appropriate. The risk of bleedings may be increased in  
certain patient groups, e.g. those patients with uncontrolled severe arterial hypertension and/or on  
concomitant treatment affecting haemostasis (see section 4.4 Haemorrhagic risk). Menstrual  
bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as  
weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained  
shock. In some cases, as a consequence of anaemia, symptoms of cardiac ischaemia like chest  
pain or angina pectoris have been observed.  
Known complications secondary to severe bleeding such as compartment syndrome and renal  
failure due to hypoperfusion have been reported for RIVAHET. Therefore, the possibility of  
haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows  
continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to  
report any suspected adverse reactions via the “6.04 Adverse Drug Reactions Reporting Form”,  
found online under SAHPRA’s publications: https://www.sahpra.org.za and to the Holder of  
certificate of registration through the mail: pvg.cdma@heterogroups.com.  
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4.9 Overdose  
Cases of overdose up to 1960 mg have been reported. In case of overdose, observe your patient  
carefully for bleeding complications or other adverse reactions (see section ‘Management of  
bleeding’). Due to limited absorption a ceiling effect with no further increase in average plasma  
exposure is expected at supratherapeutic doses of 50 mg or above.  
A specific antidote antagonising the pharmacodynamic effect of RIVAHET is not available in South  
Africa. The use of activated charcoal to reduce absorption in case of RIVAHET overdose may be  
considered. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.  
Management of bleeding:  
Should a bleeding complication arise in a patient receiving RIVAHET the next administration should  
be delayed, or treatment should be discontinued as appropriate. Rivaroxaban has a half-life of  
approximately 5 to 13 hours (see section 5.2). Management should be individualised according to  
the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as  
needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with  
bleeding control procedures, fluid replacement and haemodynamic support, blood products  
(packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or  
platelets.  
If bleeding cannot be controlled by the above measures, administration of a specific procoagulant  
factor Xa inhibitor reversal agent (andexanet alfa) should be considered, such as prothrombin  
complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant  
factor VIIa (r-FVIIa). However, there is currently very limited clinical experience with the use of  
these products in individuals receiving RIVAHET. The recommendation is also based on limited  
non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated depending  
on improvement of bleeding. Depending on local availability, a consultation with a coagulation  
expert should be considered in case of major bleedings (see section 5.1).  
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Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of RIVAHET.  
There is no scientific rationale for benefit or experience with systemic haemostatics (e.g.  
desmopressin, aprotinin, tranexamic acid, aminocaproic acid) in individuals receiving RIVAHET.  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
Category and Class: A 8.2 Anticoagulants  
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code:  
B01AF01.  
Mechanism of action  
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability.  
Activation of Factor X to Factor Xa (FXa) via the intrinsic and extrinsic pathway plays a central role  
in the cascade of blood coagulation. FXa directly converts prothrombin to thrombin through the  
prothrombinase complex, and ultimately, this reaction leads to fibrin clot formation and activation of  
platelets by thrombin. One molecule of FXa is able to generate more than 1000 molecules of  
thrombin due to the amplification nature of the coagulation cascade. In addition, the reaction rate of  
prothrombinase-bound FXa increases 300,000-fold compared to that of free FXa and causes an  
explosive burst of thrombin generation.  
Selective inhibitors of FXa can terminate the amplified burst of thrombin generation. Consequently,  
several specific and global clotting tests are affected by rivaroxaban. Dose dependent inhibition of  
Factor Xa activity was observed in humans.  
Pharmacodynamic effects  
Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close  
correlation to plasma concentrations (r value equals 0,98) if Neoplastin® is used for the assay.  
Other reagents would provide different results. The readout for PT is to be done in seconds,  
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because the INR (International Normalised Ratio) is only calibrated and validated for coumarins  
and cannot be used for any other anticoagulant.  
In patients undergoing major orthopaedic surgery, the 5/95 percentiles for PT, 2 - 4 hours after  
tablet intake (i.e. at the time of maximum effect), ranged from 13 to 25 seconds.  
The activated partial thomboplastin time (aPTT) and HepTest® are also prolonged dose-  
dependently; however, they are not recommended to assess the pharmacodynamics effect of  
rivaroxaban.  
Anti-Factor Xa activity is also influenced by rivaroxaban; however, no standard for calibration is  
available.  
There is no need for monitoring of coagulation parameters during treatment with rivaroxaban.  
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the  
5/95 percentiles for PT (Neoplastin®) 2 - 4 hours after tablet intake (i.e. at the time of maximum  
effect) for 15 mg rivaroxaban twice daily ranged from 17 to 32s and for 20 mg rivaroxaban once  
daily from 15 to 30s. In patients with non-valvular atrial fibrillation receiving rivaroxaban for the  
prevention of stroke and systemic embolism, the 5/95 percentiles for PT (Neoplastin®) 1 to 4 hours  
after tablet intake (i.e. at the time of maximum effect) in patients treated with 20 mg once daily  
ranged from 14 to 40s and in patients with moderate renal impairment treated with 15 mg once  
daily from 10 to 50s.  
The activated partial thromboplastin time (aPTT) and HepTest® are also prolonged dose-  
dependently; however, they are not recommended to assess the pharmacodynamic effect of  
rivaroxaban.  
Anti-factor Xa activity is also influenced by rivaroxaban: however, no standard for calibration is  
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available.  
5.2 Pharmacokinetic properties  
Absorption  
The absolute bioavailability of rivaroxaban is high, approximately 80 - 100 % for the 10 mg dose,  
irrespective of fasting/fed conditions. Rivaroxaban is rapidly absorbed with maximum  
concentrations (Cmax) appearing 2 - 4 hours after tablet intake.  
Administration of rivaroxaban tablets with food (high-calorie / high-fat meal) showed no significant  
food effects. Rivaroxaban 10 mg dose can be taken with or without food (see section 4.2).  
The Oral bioavailability for RIVAHET 20 tablet dose is 66 %, under fasting  
conditions. When RIVAHET 20 tablets are taken together with food, increases in mean AUC by 39  
% were observed when compared to tablet intake under fasting conditions, indicating almost  
complete absorption and high oral bioavailability. RIVAHET 15 and RIVAHET 20 should be taken  
with food (see section 4.2).  
Under fed conditions RIVAHET 15 and RIVAHET 20 tablets demonstrated dose-proportionality.  
Rivaroxaban pharmacokinetics is approximately linear up to about 15 mg once daily.  
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV %)  
ranging from 30 % to 40 %.  
Distribution  
Plasma protein binding in humans is high at approximately 92 to 95 %, with serum albumin being  
the main binding component. The volume of distribution is moderate with Vss being approximately  
50 L.  
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Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
Biotransformation  
Rivaroxaban is eliminated by metabolic degradation (approximately 2/3 of the administered dose)  
as well as by direct renal excretion of unchanged compound (approximately 1/3). Rivaroxaban is  
metabolised via CYP 3A4, CYP 2J2 and CYP-independent mechanisms. Oxidative degradation of  
the morpholinone moiety and hydrolysis of the amide bonds are the major sites of  
biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter  
proteins P-gp (P-glycoprotein) and BCRP (breast cancer resistance protein). However, it is not yet  
possible to quantify which of both proteins is more relevant for the renal secretion.  
Elimination  
Elimination of rivaroxaban and metabolites occurs via both renal and faecal routes.  
Approximately 66 % of a rivaroxaban dose is eliminated via the kidneys, with 30 - 40 % excreted as  
unchanged drug in the urine via both glomerular filtration and active renal secretion. Based on in  
vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and  
Bcrp (breast cancer resistance protein).  
Unchanged rivaroxaban is the most important compound in human plasma with no major or active  
circulating metabolites being present. With a systemic clearance of about 10 L/h rivaroxaban can  
be classified as low-clearance drug. Elimination of rivaroxaban from plasma occurred with terminal  
half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the  
elderly.  
Characteristics in specific groups of subjects or patients  
Gender/Elderly (above 65 years):  
Elderly patients exhibited higher plasma concentrations than younger patients with mean AUC  
values being approximately 1,5-fold higher, mainly due to reduced (apparent) total and renal  
clearance (see section 4.2).  
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Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
There were no clinically relevant differences in pharmacokinetics between male and female  
patients (see section 4.2).  
Different weight categories:  
Extremes in body weight (< 50 kg versus > 120 kg) had only a small influence on rivaroxaban  
plasma concentrations (less than 25 %) (see section 4.2).  
Inter-ethnic differences:  
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic,  
Japanese or Chinese patients were observed regarding pharmacokinetics and pharmacodynamics  
(see section 4.2).  
Hepatic impairment:  
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor  
changes in rivaroxaban pharmacokinetics (1,2-fold increase in rivaroxaban AUC on average),  
nearly comparable to their matched healthy control group. No relevant difference in  
pharmacodynamic properties was observed between these groups.  
In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban  
mean AUC was significantly increased by 2,3-fold compared to healthy volunteers, due to  
significantly impaired drug clearance which indicates significant liver disease. The inhibition of  
Factor Xa activity was increased by a factor of 2,6 as compared to healthy volunteers; prolongation  
of PT was similarly increased by a factor of 2,1. The global clotting test PT assesses the extrinsic  
pathway (coagulation Factors VII, X, V, II, I), of which Factors II, VII, and X are synthesised in the  
liver. The elevated PT at baseline and a significantly altered sensitivity in anticoagulant activity  
towards rivaroxaban plasma exposure (increase in slope for PT / rivaroxaban plasma concentration  
relationship by more than 2-fold) in cirrhotic patients classified as Child Pugh B indicate the  
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Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
decreased ability of the liver to synthesise coagulation factors.  
The PK/PD changes in these patients are markers for the severity of the underlying hepatic  
disease which is expected to lead to a subsequent increased bleeding risk in this patient group.  
Therefore, rivaroxaban is contra-indicated in patients with significant hepatic disease which is  
associated with coagulopathy leading to a clinically relevant bleeding risk (see section 4.3).  
No data are available for Child Pugh C patients (see sections 4.2 and 4.3).  
Renal impairment:  
There was an increase in rivaroxaban exposure being inversely correlated to the decrease in renal  
function, as assessed via creatinine clearance measurements.  
In individuals with mild (creatinine clearance 80 – 50 mL/min), moderate (creatinine clearance < 50  
– 30 mL/min) or severe (creatinine clearance < 30 mL/min) renal impairment, rivaroxaban plasma  
concentrations (AUC) were 1,4; 1,5 and 1,6-fold increased respectively as compared to healthy  
volunteers (see sections 4.2 and 4.4).  
Corresponding increases in pharmacodynamic effects were more pronounced (see sections 4.2  
and 4.4).  
In individuals with mild, moderate or severe renal impairment the overall inhibition of factor Xa  
activity was increased by a factor of 1,5; 1,9 and 2,0 respectively as compared to healthy  
volunteers; prolongation of PT was similarly increased by a factor of 1,3; 2,2 and 2,4 respectively.  
There are no data in patients with creatinine clearance < 15 ml/min. Use is not recommended in  
patients with creatinine clearance < 15 ml/min.  
Due to the underlying disease patients with severe renal impairment are at an increased risk of  
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Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
both bleeding and thrombosis. Rivaroxaban is to be used with caution in patients with severe renal  
impairment (see sections 4.2 and 4.4).  
Paediatric population  
Safety and efficacy have not been established for children and adolescents up to 18 years.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
•
•
•
•
•
•
Cellulose microcrystalline  
Crosscarmellose sodium  
Hypromellose 2910 5cps  
Lactose monohydrate  
Magnesium stearate  
Sodium lauryl sulphate  
Opadry 04F580011 White (consists of HPMC 2910/hypromellose, titanium dioxide,  
macrogol/PEG)  
•
•
•
Opadry 04F530020 Orange (consists of HPMC 2910/hypromellose, macrogol/PEG,  
titanium dioxide, iron oxide yellow, iron oxide red)  
Opadry 04F575002 Grey (consists of HPMC 2910/hypromellose, macrogol/PEG, titanium  
dioxide, ferrosoferric oxide NF/Black iron oxide, iron oxide yellow)  
Opadry 04F575000 Grey (consists of HPMC 2910/hypromellose, macrogol/PEG, titanium  
dioxide, ferrosoferric oxide NF/Black iron oxide, iron oxide yellow)  
6.2 Incompatibilities  
Not applicable.  
6.3 Shelf life  
24 months.  
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Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
6.4 Special precautions for storage  
•
•
•
Store at or below 25 °C.  
Keep the tablets in the original container until required for use.  
This medicine does not require any special storage conditions.  
6.5 Nature and contents of container  
HDPE bottle:  
Tablets are pack in a white opaque high density polyethylene container (HDPE) container with  
white opaque polypropylene child resistant closure with pulp liner.  
Pack size: 100’s  
10 mg and 20 mg  
Blister strips:  
Blister strips of clear, transparent, thermoformable, rigid PVC/PVdC forming film and plain  
aluminium lidding foil, containing 10 tablets per blister.  
Pack sizes: 10 tablets per blister. 10’s x 10 blisters and 10’s x 3 blisters packed in a box.  
15 mg  
Blister strips:  
Blister strips of clear, transparent, thermoformable, rigid PVC/PVdC forming film and plain  
aluminium lidding foil, containing 10 tablets per blister.  
Pack sizes: 10 tablets per blister. 10’s x 10 blisters and 10’s x 3 blisters packed in a box.  
Stimulated bulk pack:  
Tablets are pack in a clear transparent low density polyethylene (poly bag), plain triple laminated  
bag containing 5 grams of silica gel sachet.  
Pack size: 1000’s  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RIVAHET 10, 15 & 20  
Dosage form and strength: Film coated tablet and 10 mg, 15 mg & 20 mg  
HDPE bottle and blister strips are enclosed in an outer carton box.  
Not all pack sizes may be marketed.  
6.6 Special precautions for disposal and other handling  
No special requirements  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus  
Building No.2, First Floor  
74 Waterfall Drive  
Midrand, 2066  
Telephone number: 012 644 1220  
e-mail address: nokuthula.n@hetero.com  
8 REGISTRATION NUMBERS  
RIVAHET 10: 56/8.2/1094  
RIVAHET 15: 56/8.2/1095  
RIVAHET 20: 56/8.2/1096  
9 DATE OF FIRST AUTHORISATION  
21 January 2025  
10 DATE OF REVISION OF THE TEXT  
04 July 2025  
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