Chemical formula: C₁₈H₁₃ClFN₃ Molecular mass: 325.767 g/mol PubChem compound: 4192
Midazolam interacts in the following cases:
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.
Midazolam is metabolised by CYP3A4. Inhibitors and inducers of CYP3A4 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 maximal clinical effect of CYP3A4 inhibition will be minor, but the duration of effect may be prolonged. However after prolonged dosing 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 rectal and intramuscular administration. It is expected that these interactions will be less pronounced for the rectal than for the oral route because the gastro-intestinal tract is by-passed whereas after i.m administration the effects of CYP3A4 modulation should not substantially differ from those seen with i.v midazolam.
It is therefore recommended to carefully monitor the clinical effects and vital signs during the use of midazolam, taking into account that they may be stronger and longer after co-administration of a CYP3A4 inhibitor, be it given only once. 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.
With respect to induction, 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.
Alcohol may markedly enhance the sedative effect of midazolam, so concurrent intake should be strongly avoided.
Grapefruit juice reduces the clearance of midazolam and potentiates its action.
Hepatic impairment reduces the clearance of i.v. midazolam with a subsequent increase in terminal half-life. Therefore, the clinical effects may be stronger and prolonged. The required dose of midazolam may be reduced and proper monitoring of vital signs should be established.
Enhanced hypotensive effect with ACE-inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers, adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics.
Saquinavir and other HIV protease inhibitors: Co-administration with protease inhibitors may cause a large increase in the concentration of midazolam. Upon coadministration 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 in the above section for azole antifungals, ketoconazole.
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.
Midazolam decreases the minimum alveolar concentration (MAC) of inhalational anaesthetics.
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as midazolam with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited.
Metabolism of midazolam and other benzodiazepines is accelerated by xanthines.
Aprepitant dose dependently increased the plasma concentrations of oral midazolam by 3.3-fold after 80 mg/day associated with an increase in terminal half-life by 2-fold, therefore increasing the risk of prolonged sedation.
Atorvastatin showed a 1.4-fold increase in plasma concentrations of IV midazolam compared to control group.
Increased sedative effect with baclofen and tizanidine.
Repeat dosages of carbamezepine 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%.
Carbamazepine reduces the plasma concentrations of midazolam. Benzodiazepines may alter ie. Either increase or decrease the plasma concentrations of phenytoin.
Cimetidine, ranitidine and omeprazole have been shown to reduce the clearance of midazolam and other benzodiazepines and may potentiate their actions.
A single dose of diltiazem increased the plasma concentrations of intravenous midazolam by about 25% and the terminal half-life was prolonged by 43%.
Verapamil/diltiazem increased the plasma concentrations of oral midazolam by 3- and 4-fold, respectively. The terminal half-life of midazolam was increased by 41% and 49% respectively.
The 5-fold increase in the ratio of the CYP3A4 generated metabolite α-hydroxymidazolam to midazolam confirms its CYP3A4-inducing effect.
Erythromycin increases 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 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.
Fentanyl may reduce midazolam clearance.
Ketoconazole increased the plasma concentrations of intravenous midazolam by 5-fold while the terminal half-life increased by about 3-fold. If parenteral midazolam is coadministered with the strong CYP3A4 inhibitor ketoconazole, 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.
Voriconazole increased the exposure of intravenous midazolam by 3-fold whereas its elimination half-life increased by about 3-fold.
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.
It should be kept in mind that if midazolam is given orally, its exposure will drastically be higher than the above-mentioned ones, notably with ketoconazole, itraconazole, voriconazole.
Nefazodone increased the plasma concentrations of oral midazolam by 4.6-fold with an increase of its terminal half-life by 1.6-fold.
Nilotinib and nabilone may increase plasma concentration of midazolam.
Quinupristin/dalfopristin and telithomycin may increase plasma concentration of midazolam.
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%.
Rifampicin decreased the plasma concentrations of oral midazolam by 96% in healthy subjects and its psychomotor effects were almost totally lost.
There is no information on roxithromycin with i.v midazolam but the mild effect on the terminal half-life of oral midazolam increase of 30%, indicates that the effects on i.v midazolam may be minor.
Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reported to occur with midazolam. These reactions may occur with high doses and/or when the injection is given rapidly. The highest incidence to such reactions has been reported among children and the elderly.
Midazolam causes anterograde amnesia (frequently this effect is very desirable in situations such as before and during surgical and diagnostic procedures), the duration of which is directly related to the administered dose. Prolonged amnesia can present problems in outpatients, who are scheduled for discharge following intervention. After receiving midazolam parenterally, patients should be discharged from hospital or consulting room only if accompanied by an attendant.
Midazolam should not be used during pregnancy unless clearly necessary. It is preferable to avoid using it for caesarean.
Insufficient data are available on midazolam to assess its safety during pregnancy. Animal studies do not indicate a teratogenic effect, but foetotoxicity was observed as with other benzodiazepines. No data on exposed pregnancies are available for the first two trimesters of pregnancy.
The administration of high doses of midazolam in the last trimester of pregnancy, during labour or when used as an induction agent of anaesthesia for caesarean section has been reported to produce maternal or foetal adverse effects (inhalation risk in mother, irregularities in the foetal heart rate, hypotonia, poor sucking, hypothermia and respiratory depression in the neonate).
Moreover, infants born from mothers who received benzodiazepines chronically during the latter stage of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the post-natal period.
The risk for neonate should be taken into account in case of administration of midazolam for any surgery near the term.
Midazolam passes in low quantities into breast milk. Nursing mothers should be advised to discontinue breast-feeding for 24 hours following administration of midazolam.
Animal studies did not show an impairment of fertility.
Sedation, amnesia, impaired attention and impaired muscular function may adversely affect the ability to drive or use machines.
Prior to receiving midazolam, the patient should be warned not to drive a vehicle or operate a machine until completely recovered. The physician should decide when these activities may be resumed. It is recommended that the patient is accompanied when returning home after discharge.
Where midazolam is used concurrently with other central nervous system depressants (e.g. potent analgesics) recovery may be prolonged. Patients should therefore be assessed carefully before being allowed to go home or resume normal activities.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
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