Interactions : אינטראקציות

4.5    Interaction with other medicinal products and other forms of interaction

Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is mainly metabolized by the CYP3A4 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 (up-regulation) 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.

NON-CYP3A4-MEDIATED EFFECTS – Other interactions and effects that occur with methylprednisolone are described in Table 2 below.

Table 2 provides a list and descriptions of the most common and/or clinically important drug interactions or effects with methylprednisolone.

Table 2.        Important drug or substance interactions/effects with methylprednisolone 
Drug Class or Type            Interaction                                 Effect - DRUG or
SUBSTANCE
Macrolide Antibacterial       CYP3A4                      CYP3A4 INHIBITOR.
- TROLEANDOMYCIN              INHIBITOR                   An increase in the plasma concentration of methylprednisolone may occur. The dose
Antibacterial                                             of methylprednisolone may need to be - ISONIAZID                                               titrated to avoid steroid toxicity In addition, there is a potential effect of
- GRAPEFRUIT JUICE                                        methylprednisolone to increase the acetylation rate and clearance of isoniazid.
Antibiotic, Antitubercular    CYP3A4                      CYP3A4 INDUCER - RIFAMPIN                    INDUCER                     A decrease in the plasma concentration of methylprednisolone may occur.
Anticonvulsants                                           Co-administration may require an increase - PHENOBARBITAL                                           in methylprednisolone dosage to achieve - PHENYTOIN                                               the desired result.
Antiemetic                    CYP3A4                      CYP3A4 INHIBITORS (and - APREPITANT                  INHIBITORS                  SUBSTRATES) - FOSAPREPITANT               (and                        The hepatic clearance of SUBSTRATES)                 methylprednisolone may be inhibited or
Antifungal                                                induced, resulting in an increase or - ITRACONAZOLE                                            decrease in the plasma concentration of - KETOCONAZOLE                                            methylprednisolone. A corresponding dosage adjustment may be required. It is
Antivirals                                                possible that adverse events associated - HIV-PROTEASE                                            with the use of either drug alone may be INHIBITORS                                              more likely to occur with administration Pharmacokinetic enhancers                                 1) Protease inhibitors, such as indinavir - COBICISTAT                                              and ritonavir, may increase plasma concentrations of corticosteroids.
Calcium Channel Blocker                                   2) Corticosteroids may induce the - DILTIAZEM                                               metabolism of HIV protease inhibitors resulting in reduced plasma concentrations.
Contraceptives (oral)
- ETHINYLESTRADIOL                                        Ciclosporin / NORETHISTERONE                                          1) Mutual inhibition of metabolism occurs with concurrent use of ciclosprin and
Immunosuppressant                                         methylprednisolone, which may increase - CICLOSPORIN                                             the plasma concentrations of either or both drugs. Therefore, it is possible that adverse
Macrolide Antibacterial                                   events associated with the use of either - CLARITHROMYCIN                                          drug alone may be more likely to occur - ERYTHROMYCIN                                            upon co-administration.
2) Convulsions have been reported with concurrent use of methylprednisolone and
ciclosporin.
Anticonvulsants         CYP3A4                    CYP3A4 INDUCER (and SUBSTRATE) - CARBAMAZEPINE         INDUCER (and              The hepatic clearance of SUBSTRATE)                methylprednisolone may be inhibited or induced, resulting in an increase or decrease in the plasma concentration of methylprednisolone. A corresponding dosage adjustment may be required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with administration
Immunosuppressant       CYP3A4                    CYP3A4 SUBSTRATES
- CYCLOPHOSPHAMIDE      SUBSTRATES                The hepatic clearance of - TACROLIMUS                                      methylprednisolone may be inhibited or induced, resulting in an increase or decrease in the plasma concentration of methylprednisolone. A corresponding dosage adjustment may be required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with administration
Anticoagulants (oral)   Non-CYP3A4 mediated       The effect of methylprednisolone on oral effects                   anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids.
Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effects.
Anticholinergics                                  Corticosteroids may influence the effect of - NEUROMUSCULAR                                   anticholinergics.
BLOCKERS                                          1) 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, Musculoskeletal, for additional information.)
2) 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.
Anticholinesterases                               Steroids may reduce the effects of anticholinesterases in myasthenia gravis.
Anti-diabetics                                    Because corticosteroids may increase blood glucose concentrations, dosage adjustments of anti-diabetic agents may be required.



Aromatase inhibitors                                      Aminoglutethimide-induced adrenal - AMINOGLUTETHIMIDE                                       suppression may exacerbate endocrine changes caused by prolonged glucocorticoid treatment.
NSAIDs (non-steroidal                                     1) There may be increased incidence of anti-inflammatory drugs)                                  gastrointestinal bleeding and ulceration - high-dose ASPIRIN                                       when corticosteroids are given with (acetylsalicylic acid)                                    NSAIDs.
2) 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.
Potassium depleting agents                                When corticosteroids are administered concomitantly with potassium depleting agents (e.g. diuretics) patients should be observed closely for development of hypokalaemia.
Corticosteroids antagonize the diuretic effect of diuretics.
There is also an increased risk of hypokalaemia with concurrent use of corticosteroids with amphotericin B,
xanthines, or beta2 agonists.

Corticosteroids antagonize the hypotensive effect of all antihypertensives.

There is an increased risk of hypokalaemia when corticosteroids are given with cardiac glycosides.

The effects of corticosteroids may be reduced for 3-4 days after mifepristone.

Incompatibilities
To avoid compatibility and stability problems, it is recommended that methylprednisolone be administered separately from other compounds that are administered via the IV route of administration. Drugs that are physically incompatible in solution with methylprednisolone include allopurinol sodium, doxapram hydrochloride, tigecycline, diltiazem hydrochloride, calcium gluconate, vecuronium bromide, rocuronium bromide, cisatracurium besylate, glycopyrrolate and propofol (see section 6.2 for additional information).