Question

FSR is an 81-year-old man (103.65kg, 66.5 in) with hypertension, diabetes mellitus, anemia, kidney failure and gastroesophageal reflux. FSR uses Apixaban 5mg bid for DVT recurrence (2014, 2018). Other medicines include: Pantoprazole, Ferrous Sulfate, Insulin NPH, Lisinopril/HCTZ and Gabapentin. In November 2018, he was evaluated by his primary physician for a fungus on the right foot, classified as severe and refractory to topical antifungal treatment. She was consulted at the infectious clinic for the treatment of the fungus in view of her diabetes mellitus condition. The service infectologist recommended the use of oral therapy with Itraconazole 200mg bid for one week.

What are the possible side effects of apixaban?

What are the drug-drug interactions present, if any?

Is any adjustment required in FSR drug therapy?

Answer 1

What are the possible side effects of apixaban?

Answer 1:

Introduction:The coagulation of the blood in the intrinsic and extrinsic pathways of clotting is dependent on the factor Xa. Apixaban is a factor Xa inhibitor. it inhibits the platelet activation and clot formation by inhibiting activated factor X.hence it is used to for the prevention  of DVT. and clot formation in atrial fibrillation.

The possible side effects of apixaban are

1.nausea,

2. easy bruisability and minor bleeds like epistaxis, bleeding from wounds, cuts or gums while brushing

3. major bleeding episodes like gastro intestinal bleeding causing coffee ground vomitus or black tarry stools, intracranial bleeding causing severe headache, dizziness, fainting and intracranial bleeds with neurological impairment ,intraocular bleeding causing vision disturbances.

4.hypersensitivity reactions including skin rash,Itching, allergic edema , breathing troubles, severe anaphylactic reactions.The occurrence of severe allergic reactions to the drug is rare .

What are the drug-drug interactions present, if any?

Answer2:The drug-drug interactions present are listed below

1.Apixaban and itraconazole: moderately significant interaction:

Increase in blood apixaban levels due to decreased metabolism and decreased renal elimination {to about 50% of previous;requiring decrease in dose of apixaban ;otherwise serious bleeding issues} on administration of itraconazole.

explanation:.

Anticoagulant effect of Apixaban is dependent on its blood concentration.The metabolism of apixaban is by cyp3a 4 {20 to 25% major} pathway of metabolism. About 25-30% of the drug that is given is excreted unmetabolized by the kidneys by active renal secretion with p-glycoprotein or P-gp. Itraconazole is a potent inhibitor of CYP3a 4 and P-gp also.(as per few studies)

As a result the metabolism of apixaban is affected as also its excretion in a patient taking Itraconazole. This causes the increase in the levels of apixaban in the blood in patients taking itraconazole (to about 50% more of the earlier values without itraconazole)and increases their risk for bleeding if the dose is not adjusted( decreased)

2.Itraconazole and pantoprazole:mildly significant interaction:Decreased blood concentration and efficacy of itraconazole by pantoprazole by decreasing absorption by decreasing gastric acidity.

explanation:

Pantoprazole is a Proton pump inhibitor and acts in the body to decrease the gastric acid levels. itraconazole is a weak base and gets ionized and becomes water soluble at low pH as in gastric acidic juice. Hence stomach acidity is required for the absorption of itraconazole

Decrease in the acid levels decreases the absorption of itraconazole in the stomach and decreases its efficacy. For effective absorption of itraconazole, the acidity of the stomach has to be restored

For this reason,It is also recommended that itraconazole is taken with cola in patients who are taking antacids and have decreased levels of acidity to promote the drug absorption and action.

Is any adjustment required in FSR drug therapy?

Answer3:

Yes,adjustment required in FSR drug therapy

1..Consideration of reduction of dose of Apixaban to 2.5mg bid from 5mg bid.

explanation:The increase in the levels of apixaban in the blood in patients taking itraconazole (to about 50% more of the earlier values without itraconazole)and increased  risk for bleeding if the dose is not adjusted( decreased) merits consideration here as patient is having kidney failure and age >80 years.

2 The drug timing of itraconazole administration [2 hours before or 1 hour after] the anta acid drug pantoprazole administration should be considered in the prescription of drug therapy.

Decrease in the acid levels decreases the absorption of itraconazole in the stomach and decreases its efficacy. For effective absorption of itraconazole, the acidity of the stomach has to be restored

It is also recommended that itraconazole is taken with cola in patients since patient is taking antacid and has decreased levels of acidity to promote the drug absorption and action.