Dormicum Drug Interactions

Pharmacokinetic Drug-Drug Interaction (DDI): Film-coated tablet: (See Contraindications and General under Precautions.)
Midazolam is almost exclusively metabolized by cytochrome P450 3A (CYP3A4 and CYP3A5). Inhibitors and inducers of CYP3A have the potential to increase and decrease the plasma concentrations and, subsequently, the pharmacodynamic effects of midazolam. No other mechanism than modulation of CYP3A activity has been proven as a source for a clinically relevant pharmacokinetic drug-drug interaction with midazolam. Midazolam is not known to change the pharmacokinetics of other drugs.
When co-administered with a CYP3A inhibitor, the clinical effects of oral midazolam may be stronger and also longer lasting and a lower dose may be required. Conversely, the effect of midazolam may be weaker and last shorter when co-administered with a CYP3A inducer and a higher dose may be required.
In case of CYP3A induction and irreversible inhibition (so-called mechanism-based inhibition), the effect on the pharmacokinetics of midazolam may persist for several days up to several weeks after administration of the CYP3A modulator. Examples of mechanism-based CYP3A inhibitors include antibacterial drugs (e.g., clarithromycin, erythromycin, isoniazid), anti-retrovirals (e.g., HIV protease inhibitors such as ritonavir, including ritonavir-boosted protease inhibitors; delavirdine), calcium channel blockers (e.g., verapamil, diltiazem), tyrosine kinase inhibitors (e.g., imatinib, lapatinib, idelalisib) or the estrogen receptor modulator raloxifene.
Ethinylestradiol combined with norgestrel or gestodene did not modify exposure to midazolam to a clinically significant degree.
Drugs that inhibit CYP3A: Classification of CYP3A inhibitors: CYP3A inhibitors can be classified according to the strength of their inhibitory effect and to the importance of the clinical modifications when they are administered concomitantly with oral midazolam.
Very strong inhibitors: Midazolam AUC increased >10-fold. The following drugs fall into this category: e.g., ketoconazole, itraconazole, voriconazole, HIV protease inhibitors including ritonavir-boosted protease inhibitors.
Combination of midazolam administered orally with very strong CYP3A inhibitors is contraindicated (see Contraindications).
Strong inhibitors: Midazolam AUC increased by 5 to 10 fold. The following drugs fall into this category: e.g., high dose clarithromycin, tyrosine kinase inhibitors (such as idelalisib) and the HCV protease inhibitors boceprevir and telaprevir.
Concomitant administration of oral midazolam and boceprevir and telaprevir is contraindicated (see Contraindications).
Moderate inhibitors: Midazolam AUC increased by 2 to 5-fold. The following drugs fall into this category: e.g., fluconazole, telithromycin, erythromycin, diltiazem, verapamil, nefazodone, NK1 receptor antagonists (aprepitant, netupitant, casopitant), tabimoreline, posaconazole.
Patients receiving midazolam with strong or moderate CYP3A inhibitors require careful evaluation because the side effects of midazolam may be potentiated (see General under Precautions).
Weak inhibitors: Midazolam AUC increased by 1.25 to <2-fold. The following drugs and herbals fall into this category: e.g., fentanyl, roxithromycin, cimetidine, ranitidine, fluvoxamine, bicalutamide, propiverine, everolimus, cyclosporine, simeprevir, grapefruit juice, Echinacea purpurea, berberine as also contained in goldenseal.
Concomitant administration of midazolam with weak CYP3A inhibitors does not usually lead to a relevant change of midazolam clinical effect.
Drugs that induce CYP3A: Patients receiving a combination of midazolam with CYP3A inducers may require a higher midazolam dose in particular if midazolam is co-administered with strong CYP3A inducers. Strong CYP3A inducers (≥80% decrease in AUC) include: e.g., rifampin, carbamazepine, phenytoin, enzalutamide and mitotane with its long lasting CYP3A4-inducing effect, while moderate CYP3A inducers (50-80% decrease in AUC) include St. John's wort and weak inducers (20-50% decrease in AUC) include efavirenz, clobazam, ticagrelor, vemurafenib, quercetin and Panax ginseng.
Solution for injection: Midazolam is almost exclusively metabolized by cytochrome P450 3A (CYP3A4, CYP3A5). Inhibitors and inducers of CYP3A have the potential to increase and decrease the plasma concentrations and, subsequently, the pharmacodynamic effects of midazolam. No other mechanism than modulation of CYP3A activity has been proven as a source for a clinically relevant pharmacokinetic drug-drug interaction with midazolam.
Midazolam is not known to change the pharmacokinetics of other drugs. When co-administered with a CYP3A inhibitor, the clinical effects of midazolam may be stronger and also longer lasting and a lower dose may be required. Conversely, the effect of midazolam may be weaker and last shorter when co-administered with a CYP3A inducer and a higher dose may be required.
In case of CYP3A induction and irreversible inhibition (so-called mechanism-based inhibition), the effect on the pharmacokinetics of midazolam may persist for several days up to several weeks after administration of the CYP3A modulator. Examples of mechanism-based CYP3A inhibitors include antibacterials (e.g. clarithromycin, erythromycin, isoniazid); anti-retroviral agents [e.g. HIV protease inhibitors such as ritonavir (including ritonavir-boosted protease inhibitors), delavirdine]; calcium channel blockers (e.g., verapamil, diltiazem); tyrosine kinase inhibitors (e.g., imatinib, lapatinib, idelalisib); or the estrogen receptor modulator raloxifene and several herbal constituents (e.g. bergamottin). In contrast to other mechanism-based inhibitors, ethinylestradiol combined with norgestrel or gestodene, used for oral contraception and grapefruit juice (200 mL) did not modify exposure to midazolam to a clinically significant degree.
The range of the inhibiting/inducing potency of drugs is wide. The antifungal ketoconazole, a very potent CYP3A inhibitor, increased the plasma concentrations of I.V. midazolam by about 5-fold. The tuberculostatic drug rifampicin belongs to the strongest inducers of CYP3A and its co-administration resulted in a decrease in the plasma concentrations of intravenous midazolam by about 60%.
The administration route of midazolam also determines the magnitude of change in its pharmacokinetics due to CYP3A modulation: The change in plasma concentrations is expected to be less for intravenous compared to oral administration of midazolam because CYP3A modulation is not confined to the liver but also occurs in the intestinal wall and hence not only affects the systemic clearance, but also the bioavailability of oral midazolam.
There are no studies investigating the effect of CYP3A modulation on the pharmacokinetics of midazolam after rectal and intramuscular administration, respectively. As after rectal administration, the drug partly bypasses the liver and the expression of CYP3A in the colon is less compared to the upper gastrointestinal tract, it is expected that the change in midazolam plasma concentrations due to CYP3A modulation will be less for the rectal than for the oral route of administration. As after intramuscular administration, the drug directly enters systemic circulation, it is expected that the effects of CYP3A modulation will be similar to those for intravenous midazolam.
In line with pharmacokinetic principles, clinical studies have shown that after I.V. single dose of midazolam the change in the maximum clinical effect due to CYP3A modulation 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 CYP3A inhibition.
The following listing gives examples of clinical pharmacokinetic drug-drug interactions with midazolam after intravenous administration. Importantly, any drug shown to possess CYP3A modulating effects in vitro and in vivo, respectively, has the potential to change the plasma concentrations of midazolam and therefore its effects. The listing includes information from clinical drug-drug interaction studies for oral midazolam in case that for the co-administered drug in question no information on intravenous midazolam is available. However, as outlined previously, the change in plasma concentrations is expected to be less for intravenous compared to oral midazolam.
Drugs that inhibit CYP3A: Azole antifungals: Ketoconazole and voriconazole increased the plasma concentrations of intravenous midazolam by 5-fold and by 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 intensive care unit (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.
Fluconazole and itraconazole both increased the plasma concentrations 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, respectively.
Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold.
Macrolide antibiotics: Erythromycin resulted in an increase in the plasma concentrations of intravenous midazolam by about 1.6-2-fold associated with an increase in midazolam's terminal half-life by 1.5-1.8-fold.
Clarithromycin increased midazolam's plasma concentrations by up to 2.5-fold associated with an increase in terminal half-life by 1.5-2-fold.
Additional information from oral midazolam: Telithromycin increased the plasma levels of oral midazolam 6-fold.
Roxithromycin: The roxithromycin effects on midazolam's pharmacokinetics are less compared to erythromycin and clarithromycin. After oral administration, the plasma concentrations of midazolam were increased by about 50% compared to a 4.4- and 2.6-fold increase caused by erythromycin and clarithromycin, respectively. The mild effect on the terminal half-life of midazolam by about 30% indicates that the effects of roxithromycin on intravenous midazolam may be minor.
Intravenous anesthetics: Disposition of intravenous midazolam was also changed by intravenous propofol (AUC and half-life increased by 1.6-fold).
Protease inhibitors: Saquinavir and other HIV 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, treatment setting should follow the description previously mentioned for ketoconazole within azole antifungals.
HCV protease inhibitors: Boceprevir and telaprevir reduce midazolam clearance. This effect resulted in a 3.4-fold increase of midazolam AUC after I.V. administration and prolonged its elimination half-life 4-fold.
Histamine receptor 2 antagonists: Cimetidine increased the steady state plasma concentrations of midazolam by 26%.
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 about 43%. This was less than the 4-fold increase seen after oral administration of midazolam.
Additional 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 resulted in a 1.4-fold increase in plasma concentrations of I.V. midazolam compared to control group.
Intravenous fentanyl is a weak inhibitor of midazolam's elimination: AUC and half-life of I.V. midazolam were increased by 1.5-fold in presence of fentanyl.
Additional information from oral midazolam: Fluvoxamine resulted in a mild increase in plasma concentrations of oral midazolam (28%) while the terminal half-life doubled.
Nefazodone increased the plasma concentrations of oral midazolam by 4.6-fold with an increase in terminal half-life by 1.6-fold.
Tyrosine kinase inhibitors have been shown either in vitro (imatinib, lapatinib or after oral administration in vivo (idelalisib) to be potent inhibitors of CYP3A4. After concomitant administration of idelalisib, oral midazolam exposure was increased on average 5.4-fold.
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.
Chlorzoxazone decreased the ratio of the CYP3A generated metabolite 1'-hydroxymidazolam (also known as α-hydroxymidazolam) to midazolam indicating a CYP3A inhibiting effect.
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) (bicalutamide, everolimus, cyclosporine, simeprevir, propiverine, berberine as also contained in goldenseal). These weak interactions are expected to be further attenuated after I.V. administration.
Drugs that induce CYP3A: Rifampicin decreased the plasma concentrations of intravenous midazolam by about 60% after 7 days of rifampicin 600 mg o.d. The terminal half-life decreased by about 50-60%.
Ticagrelor is a weak CYP3A inducer but has only small effects on intravenously administered midazolam (-12%) and 4-hydoxy-midazolam (-23%) exposures.
Additional information from oral midazolam: Carbamazepine/phenytoin: 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 about 60%.
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.
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 (α-hydroxymidazolam) to the parent compound but the clinical significance of this is unknown.
Vemurafenib modulates CYP isozymes and inhibits CYP3A4 mildly: Repeat-dose administration resulted in a mean decrease of oral midazolam exposure of 32% (up to 80% in individuals).
Herbs and food: Echinacea purpurea root extract decreased plasma concentrations (AUC) of I.V. midazolam by 20% associated with a decrease in half-life of about 42%.
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%.
Additional information from oral midazolam: Quercetin (also contained in Gingko biloba) and Panax ginseng both have weak enzyme inducing effects and reduced exposure to midazolam after its oral administration to the extent of 20-30%.
Acute protein displacement: Valproic acid: Increased concentrations of free midazolam due to displacement from plasma protein binding sites by valproic acid cannot be excluded although the clinical relevance of such an interaction is not known.
Pharmacodynamic Drug-Drug Interactions (DDI): The co-administration of midazolam with other sedative/hypnotic agents, including alcohol, is likely to result in increased sedative/hypnotic effects. Examples include opiates/opioids (when they are used as analgesics, antitussives or substitutive treatments), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate; sedative antidepressants, antihistamines and centrally acting antihypertensive drugs. Midazolam decreases the minimum alveolar concentration (MAC) of inhalational anesthetics. Enhanced side effects such as sedation and cardio-respiratory depression may also occur when midazolam is co-administered with any centrally acting depressants including alcohol. Alcohol should be avoided in patients receiving midazolam (see General under Precautions). See Overdosage for warning of other central nervous system depressants, including alcohol.
Drugs increasing alertness/memory like the AchE inhibitor physostigmine reversed the hypnotic effects of midazolam. Similarly, 250 mg of caffeine partly reversed the sedative effect of midazolam.
Solution for injection: It has been shown that spinal anesthesia can increase the sedative effect of I.V. midazolam. The midazolam dose may therefore have to be reduced. When lidocaine or bupivacaine, were administered intramuscularly, the dose of I.V. midazolam required for sedation was reduced.