Drug Interactions between anisindione and macitentan / tadalafil

Nutrition and diet can affect your treatment with anisindione. Therefore, it is important to keep your vitamin supplement and food intake steady throughout treatment. For example, increasing vitamin K levels in the body can promote clotting and reduce the effectiveness of anisindione. While there is no need to avoid products that contain vitamin K, you should maintain a consistent level of consumption of these products. Foods rich in vitamin K include beef liver, broccoli, Brussels sprouts, cabbage, collard greens, endive, kale, lettuce, mustard greens, parsley, soy beans, spinach, Swiss chard, turnip greens, watercress, and other green leafy vegetables. Moderate to high levels of vitamin K are also found in other foods such as asparagus, avocados, dill pickles, green peas, green tea, canola oil, margarine, mayonnaise, olive oil, and soybean oil. However, even foods that do not contain much vitamin K may occasionally affect the action of anisindione. There have been reports of patients who experienced bleeding complications and increased INR or bleeding times after consuming large quantities of cranberry juice, mangos, grapefruit, grapefruit juice, grapefruit seed extract, or pomegranate juice. Again, you do not need to avoid these foods completely, but it may be preferable to limit their consumption, or at least maintain the same level of use while you are receiving anisindione. Talk to a healthcare provider if you are uncertain about what foods or medications you take that may interact with anisindione. It is important to tell your doctor about all medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

When anisindione is given with enteral (tube) feedings, you may interrupt the feeding for one hour before and one hour after the anisindione dose to minimize potential for interaction. Feeding formulas containing soy protein should be avoided.

Tadalafil can lower blood pressure, and combining it with alcohol may further increase this effect. You may be more likely to experience symptoms such as dizziness, lightheadedness, fainting, flushing, headache, and heart palpitations. You should avoid or limit the use of alcohol to not more than 4 alcohol-containing drinks during a small period of time while being treated with tadalafil, and use caution when getting up from a sitting or lying position. You may also want to avoid drinking large amounts of grapefruit juice, since it may increase the blood levels and effects of tadalafil. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Consumer information for this interaction is not currently available.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of macitentan, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied with grapefruit juice but has been reported for ketoconazole, a potent CYP450 3A4 inhibitor. In ten healthy subjects, coadministration of a single 10 mg oral dose of macitentan on day 5 of treatment with ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure compared to administration alone. However, the clinical significance of the interaction is unclear. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Until further information is available, patients receiving macitentan therapy should avoid the consumption of grapefruit or grapefruit juice.

Using anisindione together with ethanol (alcohol) can cause you to bleed more easily. If you take anisindione you should avoid large amounts of alcohol, but moderate consumption (one to two drinks per day) are not likely to affect the response to anisindione if you have normal liver function. You may need a dose adjustment in addition to testing of your prothrombin time or International Normalized Ratio (INR). Call your doctor promptly if you have any unusual bleeding or bruising, vomiting, blood in your urine or stools, headache, dizziness, or weakness. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Rarely, vitamin supplements containing vitamin K may reduce the effectiveness of anisindione. This may be more likely to occur in individuals who have low levels of vitamin K in their blood. Before using any vitamin supplement, you should check the label to make sure it does not contain vitamin K. If it does, let your doctor know before you start using it. You may need more frequent monitoring of your INR after starting the supplement or whenever it is discontinued, and appropriate adjustments made in your dosage if necessary. It is important to tell your doctor about all other medications you use, including other nutritional supplements and herbs. Do not stop using any medications without first talking to your doctor.