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 (upregulation) or inhibition of the CYP3A4 enzyme.



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 Drug Class or Type
Interaction             Effect
- DRUG or SUBSTANCE
Antibiotic, Antitubercular
CYP3A4 INDUCERS - Drugs that induce
- RIFAMPIN                                          CYP3A4 activity generally increase - RIFABUTIN                                         hepatic clearance, resulting in decreased plasma concentration of medications that
CYP3A4 Inducer
Anticonvulsants                                      are substrates for CYP3A4. Co- administration may require an increase in
- PHENOBARBITAL methylprednisolone dosage to achieve the
- PHENYTOIN desired result.
- PRIMIDONE

CYP3A4 INDUCERS – see box above
CYP3A4 SUBSTRATES - In the presence of another CYP3A4 substrate,
the hepatic clearance of
Anticonvulsant
CYP3A4 Inducer (and     methylprednisolone may be affected, with
Substrate)              corresponding dosage adjustments
- CARBAMAZEPINE required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with co-administration.

Macrolide Antibacterial
- TROLEANDOMYCIN
CYP3A4 INHIBITORS - Drugs that inhibit CYP3A4 activity generally
- GRAPEFRUIT JUICE decrease hepatic clearance and increase the plasma concentration of CYP3A4
Calcium Antagonist substrate medications, such as methylprednisolone. In the presence of a
- MIBEFRADIL                CYP3A4 Inhibitor
CYP3A4 inhibitor, the dose of methylprednisolone may need to be
Histamine H2 receptor titrated to avoid steroid toxicity.
Antagonist

- CIMETIDINE
Antibacterial                                        In addition, there is a potential effect of methylprednisolone to increase the
- ISONIAZID acetylation rate and clearance of isoniazid.
Antiemetic                                           CYP3A4 INHIBITORS – see box above CYP3A4 SUBSTRATES - In the
- APREPITANT                                        presence of another CYP3A4 substrate, - FOSAPREPITANT                                     the hepatic clearance of CYP3A4 Inhibitor (and
Substrate)              methylprednisolone may be affected, with
Antifungal                                           corresponding dosage adjustments required. It is possible that adverse events
- ITRACONAZOLE associated with the use of either drug
- KETOCONAZOLE alone may be more likely to occur with


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                                                     co-administration.
Calcium Channel Blocker
(1) Mutual inhibition of metabolism
- DILTIAZEM                                        occurs with concurrent use of ciclosporin and methylprednisolone, which may increase the plasma concentrations of
Contraceptives (oral) either or both drugs. Therefore, it is possible that adverse events associated
- ETHINYLESTRADIOL/ with the use of either drug alone may be
NORETHINDRONE more likely to occur upon co- administration.
Immunosuppressant

- CICLOSPORIN (1)                                  (2) Protease inhibitors, such as indinavir and ritonavir, may increase plasma
Macrolide Antibacterial                             concentrations of corticosteroids.

- CLARITHROMYCIN                                   (3) Corticosteroids may induce the - ERYTHROMYCIN                                     metabolism of HIV-protease inhibitors resulting in reduced plasma
Antivirals                                          concentrations.

- HIV-PROTEASE
INHIBITORS (2) (3)
Pharmacokinetic enhancers
-COBICISTAT

CYP3A4 SUBSTRATES - In the presence of another CYP3A4 substrate,
the hepatic clearance of
Immunosuppressant methylprednisolone may be affected, with
CYP3A4 Substrate      corresponding dosage adjustments
- CYCLOPHOSPHAMIDE required. It is possible that adverse events
- TACROLIMUS associated with the use of either drug alone may be more likely to occur with co-administration.
(4) There may be increased incidence of gastrointestinal bleeding and ulceration when corticosteroids are given with
NSAIDs.
NSAIDs (nonsteroidal anti- inflammatory drugs) (4)
Non-CYP3A4-mediated   (5) Methylprednisolone may increase the effects               clearance of high-dose aspirin, which can
- high-dose ASPIRIN (5) lead to decreased salicylate serum levels.
(acetylsalicylic acid)
Discontinuation of methylprednisolone treatment can lead to raised salicylate serum levels, which could lead to an increased risk of salicylate toxicity.



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                                                                    (6) 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
Anticholinergics (6) information.)
- NEUROMUSCULAR
(7) Antagonism of the neuromuscular
BLOCKERS (7) blocking effects of pancuronium and vecuronium has been reported in patients taking corticosteroids. This interaction may be expected with all competitive neuromuscular blockers.

Steroids may reduce the effects of
Anticholinesterases anticholinesterases in myasthenia gravis.
Because corticosteroids may increase blood glucose concentrations, dosage
Anti-diabetics adjustments of anti-diabetic agents may be required.

The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close
Anticoagulants (oral) monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

When corticosteroids are administered concomitantly with potassium-depleting agents (i.e. diuretics), patients should be observed closely for development of
Potassium-depleting agents hypokalaemia. There is also an increased risk of hypokalaemia with concurrent use of corticosteroids with amphotericin B,
xanthenes, or beta2 agonists.
Aminoglutethimide-induced adrenal
Aromatase inhibitors suppression may exacerbate endocrine changes caused by prolonged
-AMINOGLUTETHIMIDE glucocorticoid treatment.