Drug Interactions between ephedrine / phenobarbital / potassium iodide / theophylline and sarilumab

MONITOR: Barbiturates may decrease serum levels and therapeutic effects of the methylxanthines. The mechanism is barbiturate induction of CYP450 3A4 and 1A2 hepatic metabolism of methylxanthines.

MANAGEMENT: Close observation for clinical and laboratory evidence of decreased methylxanthine effect is indicated if these drugs must be used together. Patients should be advised to notify their physician if they experience a worsening of their respiratory symptoms.

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MONITOR: Plasma concentrations of drugs that are CYP450 substrates may decrease following the initiation of interleukin (IL) inhibitors, tumor necrosis factor (TNF) blockers, or interferon (IFN) inhibitors in patients with chronic inflammatory diseases. Because the formation of hepatic CYP450 enzymes is down-regulated during infection and chronic inflammation by increased levels of certain cytokines (e.g., interleukins-1, -6, and -10; tumor necrosis factor alpha; interferons), treatment targeting these cytokines may restore or normalize CYP450 enzyme levels resulting in increased metabolism of these drugs. In vitro studies showed that tocilizumab, an IL-6 inhibitor, has the potential to impact expression of various hepatic microsomal enzymes including CYP450 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. Its effects on CYP450 2C8 or transporters is unknown. In vivo studies with omeprazole (a substrate of CYP450 2C19 and 3A4) and simvastatin (a substrate of CYP450 3A4 and OATP 1B1) showed decreases of up to 28% and 57% in systemic exposure, respectively, one week following a single dose of tocilizumab. Likewise, simvastatin and simvastatin acid exposures decreased by 45% and 36%, respectively, in 17 patients with rheumatoid arthritis one week following a single 200 mg subcutaneous dose of sarilumab, another IL-6 inhibitor. A role for other interleukins such as IL-12, IL-17A, or IL-23 in the regulation of CYP450 enzymes has not been established, and it is not known whether antagonists of these interleukins would similarly affect CYP450 metabolism. Risankizumab and tildrakizumab, both IL-23 antagonists, demonstrated no clinically significant effects when tested with CYP450 probe substrates such as caffeine (1A2), warfarin (2C9), omeprazole (2C19), dextromethorphan (2D6), metoprolol (2D6), and midazolam (3A4) in study subjects with plaque psoriasis.

MANAGEMENT: Caution is advised when treatments targeting cytokines such as interleukins, tumor necrosis factors, or interferons are prescribed to patients receiving concomitant drugs that are CYP450 substrates, particularly those with narrow therapeutic ranges (e.g., antiarrhythmics, anticonvulsants, immunosuppressants, theophylline) or sensitive substrates where decreases in plasma levels may be significant or undesirable (e.g., oral contraceptives, statins, benzodiazepines, opioids). Clinical and/or laboratory monitoring should be considered following the initiation or withdrawal of such treatments, and the dosage(s) of the CYP450 substrate(s) adjusted accordingly. Clinicians should note that the effects of IL inhibitors, TNF blockers, and IFN inhibitors on CYP450 activities may persist for several weeks after stopping therapy.

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MONITOR: Plasma concentrations of drugs that are CYP450 substrates may decrease following the initiation of interleukin (IL) inhibitors, tumor necrosis factor (TNF) blockers, or interferon (IFN) inhibitors in patients with chronic inflammatory diseases. Because the formation of hepatic CYP450 enzymes is down-regulated during infection and chronic inflammation by increased levels of certain cytokines (e.g., interleukins-1, -6, and -10; tumor necrosis factor alpha; interferons), treatment targeting these cytokines may restore or normalize CYP450 enzyme levels resulting in increased metabolism of these drugs. In vitro studies showed that tocilizumab, an IL-6 inhibitor, has the potential to impact expression of various hepatic microsomal enzymes including CYP450 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. Its effects on CYP450 2C8 or transporters is unknown. In vivo studies with omeprazole (a substrate of CYP450 2C19 and 3A4) and simvastatin (a substrate of CYP450 3A4 and OATP 1B1) showed decreases of up to 28% and 57% in systemic exposure, respectively, one week following a single dose of tocilizumab. Likewise, simvastatin and simvastatin acid exposures decreased by 45% and 36%, respectively, in 17 patients with rheumatoid arthritis one week following a single 200 mg subcutaneous dose of sarilumab, another IL-6 inhibitor. A role for other interleukins such as IL-12, IL-17A, or IL-23 in the regulation of CYP450 enzymes has not been established, and it is not known whether antagonists of these interleukins would similarly affect CYP450 metabolism. Risankizumab and tildrakizumab, both IL-23 antagonists, demonstrated no clinically significant effects when tested with CYP450 probe substrates such as caffeine (1A2), warfarin (2C9), omeprazole (2C19), dextromethorphan (2D6), metoprolol (2D6), and midazolam (3A4) in study subjects with plaque psoriasis.

MANAGEMENT: Caution is advised when treatments targeting cytokines such as interleukins, tumor necrosis factors, or interferons are prescribed to patients receiving concomitant drugs that are CYP450 substrates, particularly those with narrow therapeutic ranges (e.g., antiarrhythmics, anticonvulsants, immunosuppressants, theophylline) or sensitive substrates where decreases in plasma levels may be significant or undesirable (e.g., oral contraceptives, statins, benzodiazepines, opioids). Clinical and/or laboratory monitoring should be considered following the initiation or withdrawal of such treatments, and the dosage(s) of the CYP450 substrate(s) adjusted accordingly. Clinicians should note that the effects of IL inhibitors, TNF blockers, and IFN inhibitors on CYP450 activities may persist for several weeks after stopping therapy.

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Ephedrine-methylxanthine combinations are used for the treatment of asthma but the efficacy of the combination has been questioned. This combination may lead to increased xanthine side effects. The mechanism is unknown, but may be related to synergistic pharmacologic effects. Patients using this combination should be closely monitored for side effects such as nausea, vomiting, tachycardia, nervousness, or insomnia. If side effects are noted, the dosage of the xanthine may need to be decreased.

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