High risk medicines

DOACs have several clinically significant interactions with other medicines.

An MHRA Drug Safety Alert highlights the risk of increased bleeding when DOACs are used with certain medicines.

Conversely, some medicines may interact to reduce the blood levels of DOACs. A reduction of DOAC levels in the body may increase the risk of thrombosis.

Medicines associated with a high bleeding risk may have an additive effect with DOACs increasing the risk of prolonged and excessive bleeding.

Review the interaction on a case-by-case basis as the management advice may vary for different people.

Mechanism of interactions with DOACs

The main mechanism of interactions with DOACs involves how they are metabolised.

There are differences in the way individual DOACs are metabolised but they generally involve the cytochrome P450 isoenzyme system (CYP) and/or permeability glycoprotein (P-gp).

Interactions with DOACs often arise when medicines increase or decrease the activity of CYP450 enzymes or P-gp.

However, some interactions can occur with medicines which also impair haemostasis.

Apixaban

Apixaban is mainly metabolised by CYP3A4/5 and is a substrate of P-gp.

Apixaban blood levels are impacted by medicines that are strong inhibitors or inducers of both CYP3A4 and P-gp.

Dabigatran

Dabigatran is not metabolised by the CYP450 system and is a substrate of P-gp.

Dabigatran blood levels are impacted by medicines that are strong inhibitors or inducers of P-gp.

Edoxaban

Edoxaban is weakly metabolised by CYP3A4/5 and is a substrate of P-gp.

Edoxaban blood levels are impacted by medicines that are strong inhibitors or inducers of P-gp.

Rivaroxaban

Rivaroxaban is mainly metabolised by CYP3A4 and is a substrate of P-gp.

Rivaroxaban blood levels are impacted by medicines that are strong inhibitors or inducers of both CYP3A4 and P-gp.

Counselling

Individuals should be advised on what adverse effects to be aware of if co-administration of interacting medicines with DOACs is unavoidable. This decision must be based on the balance of risks and benefits, in discussion with the individual.

Increased risk of bleeding

Advise individuals to monitor and seek medical attention for signs of bleeding and anaemia. Symptoms includes:

• increased bruising
• prolonged bleeding
• blood in urine or stools

This is particularly important for elderly people and people with renal impairment.

Gastroprotection

Consider prescribing gastroprotection in people who also have additional risk factors for bleeding.

Risk of thrombosis

Advise individuals to monitor and seek medical attention for signs of blood clots (thrombosis).

Deep vein thrombosis (DVT)

Symptoms of DVT include:

• throbbing pain or swelling in one leg (rarely both legs)
• warm skin, red and/or darkened skin around the painful area
• swollen veins that are hard or sore when you touch them

Pulmonary embolism (PE)

Symptoms of PE include:

• difficulty breathing that comes on suddenly
• worsening chest pain when breathing in
• coughing up blood

Specific recommendations

The following resource contains specific recommendations for medicines that interact with DOACs: