Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic Interactions
Midazolam is metabolised by CYP3A4. Inhibitors and inducers of CYP3A have the potential to respectively increase and decrease the plasma concentrations, and subsequently the effects of midazolam thus requiring dose adjustments accordingly.

Pharmacokinetic interactions with CYP3A4 inhibitors or inducers are more pronounced for oral as compared to i.v. midazolam, in particular since CYP3A4 also exists in the upper gastro-intestinal tract.
This is because for the oral route both systemic clearance and availability will be altered while for the parenteral route only the change in the systemic clearance becomes effective. After a single dose of i.v.
midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. However, after prolonged dosing of midazolam, both the magnitude and duration of effect will be increased in the presence of CYP3A4 inhibition.

There are no available studies on CYP3A4 modulation on the pharmacokinetics of midazolam after intramuscular administration. It is expected that after i.m. administration the effects of CYP3A4 modulation should not substantially differ from those seen with i.v. midazolam.

When co-administered with a CYP3A4 inhibitor the clinical effects of midazolam may be stronger and longer lasting, and a lower dose may be required. Notably, administration of high doses or long-term infusions of midazolam to patients receiving strong CYP3A4 inhibitors, e.g. during intensive care, may result in long- lasting hypnotic effects, delayed recovery and respiratory depression, thus requiring dose adjustments. It is recommended to carefully monitor the clinical effects and vital signs during the use of midazolam with a CYP3A4 inhibitor. Interactions between midazolam and medicinal products that inhibit CYP3A4 are listed in Table 2.


The effect of midazolam may be weaker and shorter lasting when co-administered with a CYP3A inducer and a higher dose may be required. Interactions between midazolam and medicinal products that induce CYP3A4 are listed in Table 3.

It should be considered that the inducing process needs several days to reach its maximum effect and also several days to dissipate. Contrary to a treatment of several days with an inducer, a short-term treatment is expected to result in less apparent DDI with midazolam. However, for strong inducers a relevant induction even after short- term treatment cannot be excluded.

Midazolam is not known to change the pharmacokinetics of other drugs.

Table 2: Interactions between midazolam and medicinal products that inhibit CYP3A Medicinal product               Interaction with Intravenous Midazolama b
Azole antifungals
Ketoconazole,                   Ketoconazole and voriconazole increased the plasma concentrations of Voriconazole                    intravenous midazolam by 5-fold and 3-4-fold respectively, while the terminal half-life increased by about 3-fold. If parenteral midazolam is co-administered with these strong CYP3A inhibitors, it should be done in an ICU or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Staggered dosing and dosage adjustment should be considered, especially if more than a single i.v. dose of midazolam is administered. The same recommendation may apply also for other azole antifungals, since increased sedative effects of i.v.
midazolam, although lesser, are reported.
Fluconazole,                    Fluconazole and itraconazole both increased the plasma concentrations Itraconazole                    of intravenous midazolam by 2-3-fold associated with an increase in terminal half-life by 2.4- fold for itraconazole and 1.5-fold for fluconazole.
Posaconazole                    Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold.
Macrolide antibiotics
Erythromycin                    Erythromycin resulted in an increase in the plasma concentrations of intravenous midazolam by about 1.6- 2-fold associated with an increase of the terminal half- life of midazolam by 1.5-1.8-fold.
Clarithromycin                  Clarithromycin increased the plasma concentrations of midazolam by up to 2.5-fold associated with an increase in terminal half-life by 1.5-2-fold.
Telithromycin,                  Information from oral midazolam
Roxithromycin                   Telithromycin increased the plasma levels of oral midazolam 6-fold.
While no information on roxithromycin with i.v. midazolam is available, the mild effect on the terminal half-life of oral midazolam tablet,
increasing by 30%, indicates that the effects of roxithromycin on intravenous midazolam may be minor.
Intravenous anaesthetics
Propofol                        Intravenous propofol increased the AUC and half-life of intravenous midazolam by 1.6-fold.


Protease inhibitorsc
Saquinavir and other HIV         Co-administration with protease inhibitors may cause a large increase in (human immunodeficiency          the concentration of midazolam.
virus) protease inhibitors


Upon co-administration with ritonavir-boosted lopinavir, the plasma concentrations of intravenous midazolam increased by 5.4-fold,
associated with a similar increase in terminal half-life.
If parenteral midazolam is co-administered with HIV protease inhibitors, the advice given above for the azole antifungals,
ketoconazole and voriconazole should be followed.
Hepatitis C virus (HCV)          Boceprevir and telaprevir reduce midazolam clearance. This effect protease inhibitors              resulted in a 3.4-fold increase of midazolam AUC after i.v.
administration and prolonged its elimination half-life 4-fold.
Calcium channel blockers

Diltiazem                        A single dose of diltiazem given to patients undergoing coronary artery bypass grafting increased the plasma concentrations of intravenous midazolam by about 25% and the terminal half-life was prolonged by
43%. This was less than the 4-fold increase seen after oral administration of midazolam.
Verapamil                        Information from oral midazolam
Verapamil increased the plasma concentrations of oral midazolam by 3- fold. The terminal half-life of midazolam was increased by 41%.
Various drugs/herbs

Atorvastatin                     Atorvastatin resulted in a 1.4-fold increase in plasma concentrations of i.v. midazolam compared to control group.
Fentanyl                         Intravenous fentanyl is a weak inhibitor of midazolam elimination: AUC and half-life of i.v. midazolam were increased by 1.5-fold in the presence of fentanyl.
Nefazodone                       Information from oral midazolam
Nefazodone increased the plasma concentrations of oral midazolam by
4.6-fold with an increase of its terminal half-life by 1.6-fold.
Tyrosine kinase inhibitors       Information from oral midazolam
Tyrosine kinase inhibitors have been shown to be potent inhibitors of CYP3A4 in vitro (imatinib, lapatinib) or in vivo (idelalisib). After concomitant administration of idelalisib, oral midazolam exposure was increased on average 5.4-fold.
NK1 receptor antagonists         Information from oral midazolam
NK1 receptor antagonists (aprepitant, netupitant, casoprepitant) dose dependently increased the plasma concentrations of oral midazolam up to about 2.5-3.5- fold and increased terminal half-life by approximately 1.5-2-fold.
Other                            Information from oral midazolam
For a number of drugs or herbal medicines, a weak interaction with midazolam’s elimination was observed with concomitant changes in its exposure (< 2-fold change in AUC) (everolimus, cyclosporine,
simeprevir, propiverine). These weak interactions are expected to be further attenuated after i.v. administration.
 a
For some interactions, additional information using orally administered midazolam is provided.
Interactions with CYP3A inhibitors are more pronounced for oral as compared to i.v. midazolam.
Midazolam ampoules are not indicated for oral administration.
b
If midazolam is given orally with an azole antifungal (particularly ketoconazole, itraconazole or voriconazole), its exposure will be drastically higher compared to intravenous administration.


c
Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Therefore protease inhibitors should not be co- administered with orally administered midazolam.

Table 3: Interactions between midazolam and medicinal products that induce CYP3A 
Medicinal product                   Interaction with Intravenous Midazolama Rifampicin                          Rifampicin decreased the plasma concentrations of intravenous midazolam by about 60% after 7 days of rifampicin 600mg o.d. The terminal half-life decreased by about 50-60%.
Information from oral midazolam
Rifampicin decreased the plasma concentrations of oral midazolam by
96% in healthy subjects and its psychomotor effects were almost totally lost.
Carbamazepine, phenytoin            Information from oral midazolam
Repeat dosages of carbamazepine or phenytoin resulted in a decrease in plasma concentrations of oral midazolam by up to 90% and a shortening of the terminal half-life by 60%.
Mitotane, enzalutamide              Information from oral midazolam
The very strong CYP3A4 induction seen after mitotane or enzalutamide resulted in a profound and long-lasting decrease of midazolam levels in cancer patients. AUC of orally administered midazolam was reduced to
5% and 14% of normal values respectively.
Ticagrelor                          Ticagrelor is a weak CYP3A inducer and has only small effects on intravenously administered midazolam (-12%) and 4-hydroxymidazolam
(-23%) exposures.
Clobazam, efavirenz                 Information from oral midazolam
Clobazam and Efavirenz are weak inducers of midazolam metabolism and reduce the AUC of the parent compound by approximately 30%.
There is a resulting 4-5-fold increase in the ratio of the active metabolite (1’-hydroxymidazolam) to the parent compound but the clinical significance of this is unknown.
Vemurafenib                         Information from oral midazolam
Vemurafenib modulates CYP isozymes and induces CYP3A4 mildly:
Repeat-dose administration resulted in a mean decrease of oral midazolam exposure of 39% (up to 80% in individuals).
Herbs and food
St John’s Wort                      St John’s Wort decreased plasma concentrations of midazolam by about 20-40% associated with a decrease in terminal half-life of about 15-17%.
Depending on the specific St John’s Wort extract, the CYP3A4-inducing effect may vary.
Quercetin                           Information from oral midazolam
Quercetin (also contained in ginkgo biloba) and panax ginseng both have weak enzyme inducing effects and reduced exposure to midazolam after its oral administration by approximately 20-30%.
a
For some interactions, additional information using orally administered midazolam is provided. Interactions with CYP3A inducers are more pronounced for oral as compared to i.v. midazolam. Midazolam ampoules are not indicated for oral administration.

Pharmacodynamic Drug-Drug Interactions (DDI)
The co-administration of midazolam with other sedative/hypnotic agents and CNS depressants, including alcohol, is likely to result in enhanced sedation and cardio-respiratory depression.
Examples include opiate derivatives (be they used as analgesics, antitussives or substitutive treatments), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, 

etomidate; sedative antidepressants, non recent H1-antihistamines and centrally acting antihypertensive drugs.
Alcohol may markedly enhance the sedative effect of midazolam. Alcohol intake should be strongly avoided in case of midazolam administration (see section 4.4).
Midazolam decreases the minimum alveolar concentration (MAC) of inhalational anaesthetics.