5-HT3-receptor antagonists

5-HT3-receptor antagonists

5-HT3-receptor antagonists + Opioids Ondansetron reduces the analgesic efficacy of tramadol and at least double the dose was required in one clinical study. This resulted in more vomiting despite the

ondansetron. Although not tested, other 5-HT3-receptor antagonists would be expected to interact similarly.

It would seem prudent to use alternative analgesics if ondansetron is required.

5-HT3-receptor antagonists + Phenobarbital Rifampicin (rifampin) appears to reduce ondansetron exposure: phenobarbital would be expected to interact similarly. The Australian manufacturer of tropisetron states that drugs known to induce hepatic enzymes might lower tropisetron concentrations: they name phenobarbital. Note that as primidone is metabolised to phenobarbital it would be expected to interact similarly.

The US manufacturer of ondansetron states that no ondansetron dose adjustment is necessary on concurrent use with phenobarbital; however, it may be prudent to monitor the outcome of concurrent use to assess ondansetron efficacy, increasing the ondansetron dose if necessary. Until more is known, it would seem prudent to use similar caution with tropisetron and phenobarbital.

5-HT3-receptor antagonists + Phenytoin A preliminary report of a controlled study reported a marked reduction in ondansetron exposure in patients taking long-term phenytoin, when compared with control H subjects. The Australian manufacturer of tropisetron states that drugs known to induce hepatic enzymes might lower tropisetron concentrations: phenytoin would be expected to interact in this way. Fosphenytoin, a prodrug of phenytoin, may interact similarly.

The US manufacturer of ondansetron states that no ondansetron dose adjustment is necessary on concurrent use with phenytoin; however, it may be prudent to monitor the outcome of concurrent use to assess ondansetron efficacy, increasing the ondansetron dose if necessary. Until more is known, it would seem prudent to use similar caution with the concurrent use of tropisetron and phenytoin.

5-HT3-receptor antagonists + Rifampicin (Rifampin) Rifampicin causes a modest to marked reduction in the exposure to ondansetron. The Australian manufacturer of tropisetron states that drugs known to induce hepatic enzymes (they name rifampicin) might lower tropisetron concentrations.

The US manufacturer of ondansetron states that no ondansetron dose adjustment is necessary on concurrent use with rifampicin; however, it may be prudent to monitor the outcome of concurrent use to assess ondansetron efficacy, increasing the ondansetron dose if necessary. Until more is known, it would seem prudent to use similar caution with the concurrent use of tropisetron and rifampicin.

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5-HT3-receptor antagonists + SSRIs Symptoms similar to serotonin syndrome have been reported in two patients receiving paroxetine and ondansetron or sertraline and dolasetron. It has been suggested that a

variant of serotonin syndrome, page 522, may rarely be seen when 5-HT3-receptor antagonists and SSRIs are given together.

The general significance of this interaction is unclear, however bear the possibility of serotonin syndrome in mind if similar adverse effects occur, including agitation, confusion and tremor.

Hydralazine

Hydralazine + NSAIDs Indometacin abolished the hypotensive effects of intravenous hydralazine in one study, but did not affect it in another.

Although information is limited, various NSAIDs have been reported to reduce the efficacy of other antihypertensive drug classes. It would be prudent to monitor the concurrent use of hydralazine and NSAIDs.

H

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Imipenem

Imipenem + Valproate Case reports describe reduced valproate levels after imipenem was given. This has led to seizures. Although evidence is limited, this is in line with the way other carbapenems interact.

Avoid concurrent use if possible. If it is essential, consider using intravenous valproate (which was successfully substituted in some cases) and monitor valproate levels,adjusting the valproate dose if needed. Consider using another antibacterial, or an alternative to valproate; limited evidence suggests that carbamazepine and phenytoin are not affected. Note that imipenem should be used with caution in patients with a history of seizures.

Inotropes and Vasopressors

Inotropes and Vasopressors + Linezolid Because of its weak MAO-inhibitory properties, the manufacturers of linezolid suggest that it may interact with adrenaline (epinephrine), dopamine, dobutamine, and noradrenaline (norepinephrine) in the same way as the non-selective MAOIs. However, the evidence available suggests that blood pressure rises are only very moderate and certainly unlikely to be of the hypertensive crisis proportions seen with the non-selective MAOIs.

The manufacturers contraindicate the use of sympathomimetics with linezolid unless there are facilities available for close observation of the patient and monitoring of blood pressure.

Inotropes and Vasopressors + MAO-B inhibitors A case report describes a hypertensive reaction attributed to the concurrent use of dopamine and selegiline.

The manufacturers of selegiline recommend that dopamine should be used cautiously, if at all, in patients who are receiving selegiline long-term or who have received selegiline in the 2 weeks before needing dopamine.

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Inotropes and Vasopressors + MAOIs Dopamine, Dopexamine, Metaraminol or Phenylephrine Metaraminol and phenylephrine are vasopressors with both direct and indirect sympathomimetic actions. This means that it may cause serious and potentially fatal hypertensive reactions in patients taking MAOIs. Dopamine and dopexamine may possibly interact similarly.

Avoid the use of these vasopressors in patients who are either taking MAOIs or who have stopped taking them in the previous 2 weeks. One UK manufacturer of dopamine suggests that patients who have been taking an MAOI should be given a starting dose of dopamine that is one-tenth of the usual dose.

Other inotropes and vasopressors The pressor effects of inotropes and vasopressors with indirect sympathomimetic actions, such as adrenaline (epinephrine), isoprenaline (isoproterenol), noradrenaline (norepinephrine) and methoxamine may be unchanged or only moderately increased in patients taking MAOIs. The increase may be somewhat greater in those who show a significant hypotensive response to the MAOI. Dobutamine would be expected to interact similarly.

Although this interaction is unlikely to be important in most patients, some may experience greater effects. The manufacturers of the MAOIs contraindicate concurrent use, although some consider this overly cautious.

Inotropes and Vasopressors + Phenytoin There is some limited evidence that patients needing dopamine to support their blood pressure can become severely hypotensive if phenytoin is added to their treatment.

I Blood pressure is doubtless being monitored in patients receiving dopamine, and should be measured when phenytoin is given intravenously. However, more frequent monitoring may be necessary as this interaction appears to develop rapidly.

Inotropes and Vasopressors + Tricyclics Patients taking tricyclic antidepressants show a grossly exaggerated response (hyper- tension, cardiac arrhythmias, etc.) to parenteral noradrenaline (norepinephrine), adrenaline (epinephrine), and to a lesser extent, to phenylephrine.

The parenteral use of these inotropes should, where possible, be avoided in patients taking tricyclic antidepressants. If they must be used, the rate and amount injected must be very much reduced. The risk is probably lower when drugs such as adrenaline (epinephrine) are used with a local anaesthetic for surface or infiltra- tion anaesthesia, or nerve block and anecdotal evidence suggests that concurrent use is common; however, it would still seem advisable to be aware of the potential for interaction. The effects of phenylephrine given orally or as nasal drops does not

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appear to have been studied. Nevertheless, one manufacturer of an eye drop preparation contraindicates concurrent use.

Iron

Iron + Levodopa The absorption of levodopa can be reduced by 30 to 50% by ferrous sulfate due to levodopa chelation. Therefore all iron compounds are expected to act similarly. Carbidopa levels are also reduced by iron. There is some evidence that this interaction causes a decrease in symptom control.

Be alert for any signs of reduced levodopa efficacy. If this occurs, separating the administration of the iron as much as possible seems likely to be an effective way of managing this interaction.

Iron + Levothyroxine Ferrous sulfate (and therefore probably other iron compounds) causes a reduction in the effects of levothyroxine.

Be alert for this effect if both drugs are given, and monitor thyroid function if an interaction is suspected: adjust the levothyroxine dose accordingly. The same precautions would seem appropriate with any other iron compound.

Iron + Methyldopa I The antihypertensive effects of methyldopa can be reduced by ferrous sulfate or ferrous gluconate. Most other iron compounds are expected to interact similarly.

Monitor the effects of concurrent use and increase the methyldopa dose as necessary. Separating the dosages by up to 2 hours apparently only partially reduces the effects of this interaction.

Iron + Mycophenolate One study found that oral iron compounds markedly reduced the absorption of mycophenolate. However, four subsequent studies, including one of identical design to the first study, found that oral iron compounds had no significant effect on the absorption of mycophenolate.

On balance, it would appear that oral iron compounds do not alter the pharmacokinetics of mycophenolate, and that no special precautions are required on concurrent use.

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Iron + Penicillamine The absorption of penicillamine can be reduced as much as two-thirds by oral iron.

For maximal absorption give the iron at least 2 hours after the penicillamine. Do not stop iron suddenly in a patient stabilised on penicillamine as the marked increase in absorption that follows may precipitate penicillamine toxicity.

Iron + Proton pump inhibitors Omeprazole may impair the absorption of oral iron preparations and vegetable sources of iron. Other proton pump inhibitors may interact similarly.

Many factors and disease states can affect oral iron absorption. However bear these reports in mind should a patient taking any proton pump inhibitor fail to respond to treatment with oral iron.

Iron + Quinolones Iron compounds reduce the absorption of many of the quinolones. In descending order the extent of the interaction appears to be: norfloxacin, levofloxacin, ciprofloxacin, moxifloxacin, gatifloxacin, ofloxacin/sparfloxacin. Serum levels of the antibacterial may become subtherapeutic as a result.

Most quinolones should not be taken at the same time as iron. As the quinolones are rapidly absorbed, taking them 2 hours before the iron should largely avoid this interaction. The exceptions are fleroxacin, which appears not to interact, and lomefloxacin, which seems to interact only minimally.

Iron + Tetracyclines The absorption of the tetracyclines is markedly reduced by concurrent use. I Tetracycline levels are reduced by 30 to 90% and their therapeutic effectiveness may be reduced or even abolished. The absorption of iron may also be reduced.

The extent of the reductions depends on a number of factors.

. the particular tetracycline used: tetracycline and oxytetracycline were affected the least in one study. . the time interval between the administration of the two drugs: giving the iron 3 hours before or 2 to 3 hours after the antibacterial is satisfactory with tetracycline, but one study found that even 11 hours was inadequate for doxycycline. . the particular iron compound used: the reduction in tetracycline levels with ferrous sulfate was 80 to 90%; with ferrous fumarate, succinate and gluconate, 70 to 80%; with ferrous tartrate, 50%; and with ferrous sodium edetate, 30%. This was with doses containing equivalent amounts of elemental iron.

The interaction can therefore be accommodated by separating the doses as much as possible. It would also seem logical to choose one of the iron preparations causing minimal interference, but it seems unlikely that there will be a clinically significant difference between those that are commonly available (i.e. sulfate, fumarate and gluconate).

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