Interactions : אינטראקציות

4.5      Interaction with other medicinal products and other forms of interaction
Methylprednisolone
Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is mainly metabolized by the CYP3A enzyme. CYP3A4 is the dominant enzyme of the most abundant CYP subfamily in the liver of adult humans. It catalyzes 6β-hydroxylation of steroids, the essential Phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, some of which (as well as other drugs) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.

CYP3A4 INHIBITORS – Drugs that inhibit CYP3A4 activity generally decrease hepatic clearance and increase the plasma concentration of CYP3A4 substrate medications, such as methylprednisolone. In the presence of a CYP3A4 inhibitor, the dose of methylprednisolone may need to be titrated to avoid steroid toxicity.

CYP3A4 INDUCERS – Drugs that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentration of medications that are substrates for CYP3A4. Co-administration may require an increase in methylprednisolone dosage to achieve the desired result.

CYP3A4 SUBSTRATES – In the presence of another CYP3A4 substrate, the hepatic clearance of methylprednisolone may be affected, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with co-administration.

1.      Convulsions have been reported with concurrent use of methylprednisolone and ciclosporin (CYP3A4 inhibitor and substrate). Since concurrent administration of these agents results in a mutual inhibition of metabolism (which may increase the plasma concentrations of either or both drugs), it is possible that convulsions and other adverse effects associated with the individual use of either drug may be more apt to occur.

2.      Drugs that induce hepatic enzymes, such as rifampicin (antibiotic CYP3A4 inducer),
rifabutin, carbamazepine (anticonvulsant CYP3A4 inducer and substrate), phenobarbitone and phenytoin (anticonvulsants CYP3A4 inducers), primidone, and aminoglutethimide (aromatase inhibitor) enhance the metabolism of corticosteroids and its therapeutic effects may be reduced.
Aminoglutethimide- induced adrenal suppression may exacerbate endocrine changes caused by prolonged glucocorticoid treatment.

3.      Antibiotics/Antimycotics - Drugs such as erythromycin (macrolide antibacterial CYP3A4 inhibitor and substrate), itraconazole and ketoconazole antifungal CYP3A4 inhibitors and substrates) may inhibit the metabolism of corticosteroids and thus decrease their clearance.
Troleandomycin (CYP3A4 inhibitor), as well as clarithromycin, erythromycin, itraconazole and ketoconazole (CYP3A4 inhibitors and substrates) increase the effects and the side effects of methylprednisolone.

The acetylation rate and clearance of isoniazid (CYP3A4 inhibitor), an antibacterial drug, can be increased by methylprednisolone.

4.     Steroids may reduce the effects of anticholinesterases in myasthenia gravis.

An acute myopathy has been reported with the concomitant use of high doses of corticosteroids and anticholinergics, such as neuromuscular blocking drugs (see section 4.4).

Antagonism of the neuromuscular blocking effects of pancuronium and vecuronium has been reported in patients taking corticosteroids. This interaction may be expected with all competitive neuromuscular blockers.

The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.

5.     The effect of methylprednisolone on oral anticoagulants is variable. The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding and to maintain the desired anticoagulant effects.
There are also reports of diminished effects of anticoagulants when given concurrently with corticosteroids.

6.     There may be increased incidence of gastrointestinal bleeding and ulceration when corticosteroids are given with NSAIDs. Methylprednisolone may increase the clearance of high-dose aspirin, which can lead to decreased salicylate serum levels.
Discontinuation of methylprednisolone treatment can lead to raised salicylate serum levels, which could lead to an increased risk of salicylate toxicity.

7.     Antidiabetics - Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

8.     Antiemetics - Aprepitant and fosaprepitant (CYP3A4 inhibitors and substrates).

9.     Antivirals - HIV protease inhibitors: Indinavir, ritonavir and pharmacokinetic enhancers (cobicistat) (CYP3A4 inhibitors and substrates) may increase plasma concentrations of corticosteroids. Corticosteroids may induce the metabolism of HIV- protease inhibitors resulting in reduced plasma concentrations.

10. Calcium channel blocker - Diltiazem (CYP3A4 inhibitor and substrate).

11.    Contraceptives (oral) - Ethinylestradiol/norethindrone (CYP3A4 inhibitors and substrate).

12.    Other immunosuppressants like cyclophosphamide and tacrolimus are substrates of CYP3A4.

13.    Potassium-depleting agents - When corticosteroids are administered concomitantly with potassium-depleting agents (i.e. diuretics), patients should be observed closely for development of hypokalaemia. There is also an increased risk of hypokalaemia with concurrent use of corticosteroids with amphotericin B, xanthenes, or beta2 agonists.

14.    Grapefruit juice - CYP3A4 inhibitor.

Lidocaine
Drugs which inhibit the metabolism of lidocaine (e.g., cimetidine) may cause potentially toxic plasma concentrations when lidocaine is given repeatedly in high doses over long periods of time. Such interactions have no clinical relevance during short-term treatment with lidocaine in recommended doses. Lidocaine should be used with caution in patients receiving other local anaesthetics or class Ib antiarrhythmic drugs, as the toxic effects are additive.