Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Bristol-Myers Squibb/Pfizer EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
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. Apixaban administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and 4.9).
Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery (see section 5.1).
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 also be considered. However, there is no clinical experience with the use of 4factor PCC products to reverse bleeding in paediatric and adult patients who have received apixaban.
Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see section 4.3).
The concomitant use of apixaban with antiplatelet agents increases the risk of bleeding (see section 4.5).
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.
Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with apixaban (see section 4.5).
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.
In study CV185325, no clinically important bleeding events were reported in the 12 paediatric patients treated with apixaban and ASA ≤165 mg daily concomitantly.
Apixaban has not been studied in paediatric patients with prosthetic heart valves; therefore, the use of apixaban is not recommended.
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.
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.
Apixaban should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established (for cardioversion see section 4.2).
For patients undergoing catheter ablation for atrial fibrillation, apixaban treatment does not need to be interrupted (see sections 4.2, 4.3 and 4.5).
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 avoided and if anticoagulation with apixaban must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.
No data are available on the timing of the placement or removal of neuraxial catheter in paediatric patients while on apixaban. In such cases, discontinue apixaban and consider a short acting parenteral anticoagulant.
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents 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 post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of apixaban. 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 physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. In case there is such need and based on the general PK characteristics of apixaban, a time interval of 20-30 hours (i.e., 2 x half-life) between the last dose of apixaban and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of apixaban may be given at least 5 hours after catheter removal. As with all new anticoagulant medicinal products, experience with neuraxial blockade is limited and extreme caution is therefore recommended when using apixaban in the presence of neuraxial blockade.
Apixaban 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 apixaban have not been established in these clinical situations.
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 (see also section 4.3).
Paediatric patients with severe renal impairment have not been studied and therefore should not receive apixaban (see sections 4.2 and 5.2).
Limited clinical data indicate that apixaban plasma concentrations are increased in patients with severe renal impairment (creatinine clearance 15-29 mL/min) which may lead to an increased bleeding risk. For the prevention of VTE in elective hip or knee replacement surgery (VTEp), the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), apixaban is to be used with caution in patients with severe renal impairment (creatinine clearance 15-29 mL/min) (see sections 4.2 and 5.2).
For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renal impairment (creatinine clearance 15-29 mL/min), and patients with serum creatinine ≥1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg should receive the lower dose of apixaban 2.5 mg twice daily (see section 4.2).
In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended (see sections 4.2 and 5.2).
In adults, low body weight (< 60 kg) may increase haemorrhagic risk (see section 5.2).
Apixaban has not been studied in paediatric patients with hepatic impairment.
Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).
It is not recommended in patients with severe hepatic impairment (see section 5.2).
It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see sections 4.2 and 5.2). Patients with elevated liver enzymes ALT/AST > 2 x ULN or total bilirubin ≥1.5 x ULN were excluded in clinical studies. Therefore apixaban should be used cautiously in this population (see section 5.2). Prior to initiating apixaban, liver function testing should be performed.
No clinical data are available in paediatrics patients receiving concomitant systemic treatment with strong inhibitors of both CYP 3A4 and P-gp (see section 4.5).
The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). These medicinal products may increase apixaban exposure by 2-fold (see section 4.5), or greater in the presence of additional factors that increase apixaban exposure (e.g., severe renal impairment).
The concomitant use of apixaban with strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may lead to a ~50% reduction in apixaban exposure.
In a clinical study in atrial fibrillation patients, diminished efficacy and a higher risk of bleeding were observed with coadministration of apixaban with strong inducers of both CYP3A4 and P-gp compared with using apixaban alone.
In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp the following recommendations apply (see section 4.5):
No clinical data are available in paediatric patients receiving concomitant systemic treatment with strong inducers of both CYP 3A4 and P-gp (see section 4.5).
Apixaban has not been studied in clinical studies in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, it is not recommended in these patients.
Clotting tests [e.g., prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT)] are affected as expected by the mechanism of action of apixaban. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see section 5.1).
Eliquis contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Interaction studies have not been performed in paediatrics. The below mentioned interaction data was obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population.
Coadministration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean apixaban Cmax.
The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir) (see section 4.4).
Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (e.g., amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required when coadministered with agents that are not strong inhibitors of both CYP3A4 and Pgp. For example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak Pgp inhibitor, led to a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase in Cmax. Naproxen (500 mg, single dose) an inhibitor of Pgp but not an inhibitor of CYP3A4, led to a 1.5-fold and 1.6-fold increase in mean apixaban AUC and Cmax, 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 apixaban AUC and Cmax respectively.
Coadministration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean apixaban AUC and Cmax , respectively. The concomitant use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban is required during concomitant therapy with such medicinal products, however in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp apixaban should be used with caution for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE.
Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised (see section 4.4).
Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.3).
Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was coadministered with ASA 325 mg once a day.
Apixaban coadministered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) in Phase I studies did not show a relevant increase in template bleeding time, or further inhibition of platelet aggregation, compared to administration of the antiplatelet agents without apixaban. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban alone.
Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5-fold and 1.6-fold increase in mean apixaban AUC and Cmax, respectively. Corresponding increases in clotting tests were observed for apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of apixaban and naproxen.
Despite these findings, there may be individuals with a more pronounced pharmacodynamic response when antiplatelet agents are coadministered with apixaban. Apixaban should be used with caution when coadministered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk (see section 4.4).
There is limited experience of co-administration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, co-administration of these medicinal products with apixaban is not recommended (see section 4.4).
In study CV185325, no clinically important bleeding events were reported in the 12 paediatric patients treated with apixaban and ASA ≤165 mg daily concomitantly.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was coadministered with atenolol or famotidine. Coadministration of apixaban 10 mg with atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of apixaban. Following administration of the two medicinal products together, mean apixaban AUC and Cmax were 15% and 18% lower than when administered alone. The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or Cmax.
In vitro apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 >45 μM) and weak inhibitory effect on the activity of CYP2C19 (IC50 >20 μM) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 μM. Therefore, apixaban is not expected to alter the metabolic clearance of co-administered medicinal products that are metabolised by these enzymes. Apixaban is not a significant inhibitor of P-gp.
In studies conducted in healthy subjects, as described below, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, or atenolol.
Coadministration of apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P-gp substrate, did not affect digoxin AUC or Cmax. Therefore, apixaban does not inhibit P-gp mediated substrate transport.
Coadministration of single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, did not have any effect on the naproxen AUC or Cmax.
Coadministration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.
Administration of activated charcoal reduces apixaban exposure (see section 4.9).
Interaction studies have not been performed in paediatrics. The above mentioned interaction data was obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population.
There are no data from the use of apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of apixaban during pregnancy.
It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk (see section 5.3). A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from apixaban therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Studies in animals dosed with apixaban have shown no effect on fertility (see section 5.3).
Eliquis has no or negligible influence on the ability to drive and use machines.
Apixaban has been investigated in over 7 Phase III clinical studies including more than 21 000 patients: more than 5 000 patients in VTEp studies, more than 11 000 patients in NVAF studies and more than 4 000 patients in the VTE treatment (VTEt) studies, for an average total exposure of 20 days, 1.7 years and 221 days respectively (see section 5.1).
Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 2 for adverse reaction profile and frequencies by indication).
In the VTEp studies, in total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. The overall incidence of adverse reactions related to bleeding with apixaban was 10% in the apixaban vs enoxaparin studies.
In the NVAF studies, the overall incidence of adverse reactions related to bleeding with apixaban was 24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs acetylsalicylic acid study. In the apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major intraocular bleeding with apixaban was 0.18%/year.
In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was 15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study (see section 5.1).
Table 2 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 VTEp, NVAF and 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 2 for paediatric patients are derived from study CV185325, in which they received apixaban for treatment of VTE and prevention of recurrent VTE.
Table 2. 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) 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 | Common |
| Thrombocytopenia | Uncommon | Uncommon | Common | Common |
| Immune system disorders | ||||
| Hypersensitivity, allergic oedema and Anaphylaxis | Rare | Uncommon | Uncommon | Common‡ |
| Pruritus | Uncommon | Uncommon | Uncommon* | Common |
| Angioedema | Not known | Not known | Not known | Not known |
| Nervous system disorders | ||||
| Brain haemorrhage† | Not known | Uncommon | Rare | Not known |
| Eye disorders | ||||
| Eye haemorrhage (including conjunctival haemorrhage) | Rare | Common | Uncommon | Not known |
| Vascular disorders | ||||
| Haemorrhage, haematoma | Common | Common | Common | Common |
| Hypotension (including procedural hypotension) | Uncommon | Common | Uncommon | Common |
| Intra-abdominal haemorrhage | Not known | Uncommon | Not known | Not known |
| Respiratory, thoracic and mediastinal disorders | ||||
| Epistaxis | Uncommon | Common | Common | Very common |
| Haemoptysis | Rare | Uncommon | Uncommon | Not known |
| Respiratory tract haemorrhage | Not known | Rare | Rare | Not known |
| Gastrointestinal disorders | ||||
| Nausea | Common | Common | Common | Common |
| Gastrointestinal haemorrhage | Uncommon | Common | Common | Not known |
| Haemorrhoidal haemorrhage | Not known | Uncommon | Uncommon | Not known |
| Mouth haemorrhage | Not known | Uncommon | Common | Not known |
| Haematochezia | Uncommon | Uncommon | Uncommon | Common |
| Rectal haemorrhage, gingival bleeding | Rare | Common | Common | Common |
| Retroperitoneal haemorrhage | Not known | Rare | Not known | Not known |
| Hepatobiliary disorders | ||||
| Liver function test abnormal, asparate aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased | Uncommon | Uncommon | Uncommon | Common |
| Gamma- glutamyltransferase increased | Uncommon | Common | Common | Not known |
| Alanine aminotransferase increased | Uncommon | Uncommon | Common | Common |
| Skin and subcutaneous tissue disorders | ||||
| Skin rash | Not known | Uncommon | Common | Common |
| Alopecia | Rare | Uncommon | Uncommon | Common |
| Erythema multiforme | Not known | Very rare | Not known | Not known |
| Cutaneous vasculitis | Not known | Not known | Not known | Not known |
| Musculoskeletal and connective tissue disorders | ||||
| Muscle haemorrhage | Rare | Rare | Uncommon | Not known |
| Renal and urinary disorders | ||||
| Haematuria | Uncommon | Common | Common | Common |
| Reproductive system and breast disorders | ||||
| Abnormal vaginal haemorrhage, urogenital haemorrhage | Uncommon | Uncommon | Common | Very common§ |
| General disorders and administration site conditions | ||||
| Application site bleeding | Not known | Uncommon | Uncommon | Not known |
| Investigations | ||||
| Occult blood positive | Not known | Uncommon | Uncommon | Not known |
| Injury, poisoning and procedural complications | ||||
| Contusion | Common | Common | Common | Common |
| Post procedural haemorrhage (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 | Uncommon | Uncommon | Uncommon | Common |
| Traumatic haemorrhage | Not known | Uncommon | Uncommon | Not known |
* There were no occurrences of generalised pruritus in CV185057 (long term prevention of VTE).
† The term “Brain haemorrhage” encompasses all intracranial or intraspinal haemorrhages (i.e., haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages).
‡ This includes anaphylactic reaction, drug hypersensitivity, and hypersensitivity.
§ Includes heavy menstrual bleeding, intermenstrual bleeding, and vaginal haemorrhage.
The safety of apixaban has been investigated in 1 Phase I and 3 Phase II/III clinical studies including 970 patients. Of these 568 received one or more doses of apixaban for average total exposure of 1, 24, 331 and 80 days, respectively (see section 5.1). The patients received weight adjusted doses of an age-appropriate formulation of apixaban.
Overall, the safety profile of apixaban in paediatric patients 28 days to <18 years of age was similar to that in adults and was generally consistent across different paediatric age groups.
The most commonly reported adverse reactions in paediatric patients were epistaxis, and abnormal vaginal haemorrhage (see Table 2 for adverse reaction profile and frequencies by indication).
In paediatric patients, epistaxis (very common), abnormal vaginal haemorrhage (very common), hypersensitivity and anaphylaxis (common), pruritus (common), hypotension (common), haematochezia (common), aspartate aminotransferase increased (common), alopecia (common), and post procedural haemorrhage (common) were reported more frequently as compared to adults treated with apixaban, but in the same frequency category as the paediatric patients in the standard of care arm (SOC); the only exception was abnormal vaginal haemorrhage, which was reported as common in the SOC arm. In all but one case, hepatic transaminase elevations were reported in paediatric patients receiving concomitant chemotherapy for an underlying malignancy.
The use of apixaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding (see sections 4.4 and 5.1).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.