Philip D. Hansten, PharmD

Practitioners have known for almost 2 decades that oral contraceptives (OCs) consistently and substantially reduce the serum concentrations of lamotrigine and may reduce seizure control. This mechanism appears to be caused by the induction of lamotrigine glucuronidation by OCs.

Let’s look at 3 more-recent discoveries related to the interaction that provide important new insights. First, a recent case report demonstrated that the interaction may be problematic in patients with bipolar disorder as well as those with seizures. Second, there is evidence that the interaction may be mitigated by other drugs, specifically valproic acid. Finally, it appears that lamotrigine levels may also be reduced by hormone replacement therapy (HRT).

A 23-year-old woman taking an OC (1 mg norethisterone + 0.035 mg ethinyl estradiol) was started on lamotrigine 400 mg/day for bipolar disorder.

 After several weeks, her lamotrigine serum concentrations were quite low, and her bipolar disorder had not improved. She was then switched sequentially to lithium, valproic acid, and carbamazepine, but they were all ineffective, and some had adverse events. Her health care provider then substituted leuprorelin for her OC and restarted lamotrigine at the original dose (400 mg/day), leading to therapeutic lamotrigine concentrations and effective stabilization of her bipolar disorder. This case is consistent with the findings in patients taking lamotrigine for seizures, and the interaction is rated “probable” using the Drug Interaction Probability Scale.

In a prospective study in women taking lamotrigine for epilepsy, the effect of an additional antiepileptic drug on the lamotrigine—OC interaction was studied.

 In women on lamotrigine monotherapy or on lamotrigine plus carbamazepine, lamotrigine clearance fell as expected during the OC-free week. However, in patients on lamotrigine plus valproic acid, there was no change in lamotrigine clearance during the OC-free week. The study was small, and more data are needed, but it does suggest that the expected lamotrigine—OC interaction does not occur in patients also taking valproic acid.

Valproic acid is known to inhibit uridine diphosphate—glucuronyltransferase (UGT) activity, so it is possible that UGT inhibition by valproic acid interferes with the UGT induction caused by OCs. Clinically, it is important to consider that valproic acid may inhibit the lamotrigine–OC interaction because anticipatory dose adjustments of lamotrigine when starting or stopping OCs could result in lamotrigine levels that are too high, leading to adverse outcomes, or too low, leading to seizures.

In a case-control study, women taking lamotrigine with ethinyl estradiol or HRT were matched with controls taking lamotrigine without concurrent estrogen therapy. When lamotrigine serum concentration-to-dose ratios (CDRs) were calculated, both the women on ethinyl estradiol and those on HRT had significantly lower lamotrigine CDRs than women taking lamotrigine in the absence of estrogens. Given that this was a retrospective case-control study, confirmation of this effect is needed, ideally with a prospective controlled study. However, the results are consistent with a report describing 2 women on lamotrigine who developed reduced lamotrigine serum concentrations after HRT was started, one of whom had increased seizure frequency.

The effect of HRT on lamotrigine is interesting because theoretically, HRT should simply restore serum estrogen concentrations to physiologic premenopausal levels. But the available evidence does suggest that HRT may reduce lamotrigine serum concentrations and efficacy.

The ability of OCs to substantially reduce lamotrigine serum concentrations is well documented and may necessitate adjustments in lamotrigine dosege. The interaction is also likely to occur when lamotrigine is used for bipolar disorder or other indications, and some evidence suggests that it may occur with the use of HRT as well as OCs. In patients with epilepsy, the presence of valproic acid may mitigate the interaction. This means that stopping or starting valproic acid may cause the lamotrigine—OC interaction to appear or disappear, effects that are very unlikely to be accounted for by computerized clinical decision support systems.

John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD, are professors of pharmacy at the University of Washington School of Pharmacy in Seattle.

Sawagashira R, Fujii Y, Kusumi I. Clinical pharmacokinetic interactions between lamotrigine and hormonal contraceptives in bipolar I disorder. 

Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. 

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Wegner I, Wilhelm AJ, Lambrechts DA, Sander JW, Lindhout D. Effect of oral contraceptives on lamotrigine levels depends on comedication. 

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Harden CL, Herzog AG, Nikolov BG, et al. Hormone replacement therapy in women with epilepsy: a randomized, double-blind, placebo-controlled study. 

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Articles

Practitioners have known for almost 2 decades that oral contraceptives consistently and substantially reduce the serum concentrations of lamotrigine and may reduce seizure control.

Estrogens and Lamotrigine: New Developments

The combined use of valproic acid (VPA) and a carbapenem is likely to occur in patients with central nervous system infections resulting from head trauma or surgical procedures; serious systemic infections, including pneumonia; and generalized seizure disorders.

The data describing this interaction have been based primarily on case reports and retrospective studies. Nevertheless, this potential drug interaction presents a risk to patients.

VPA is primarily metabolized by glucuronidation to VPA-glucuronide, which is eliminated from the body via bile and urine. However, VPA-glucuronide can be deconjugated by acylpeptide hydrolase to the parent compound VPA.

 The conversion of VPA-glucuronide back to VPA provides for a longer half-life and duration of action for VPA. Although the mechanism responsible for the reported interaction between VPA and carbapenem has been debated, it appears that carbapenems act by inhibiting the activity of the acylpeptide hydrolase enzyme that converts VPA-glucuronide to VPA.

 This results in greater elimination, a shortened half-life, and subtherapeutic plasma concentrations of VPA, all of which represent an uncommon drug interaction mechanism that can produce clinically significant patient outcomes.

summarizes several of the larger studies of the effect of carbapenems on VPA. In addition, there have been several case reports of subtherapeutic VPA concentrations in patients treated with carbapenems. The magnitude of this interaction ranges from about a 50% to an 80% reduction in VPA plasma concentrations. This reduction has been reported to occur in as few as 24 hours after initiation of the carbapenem. The half-life of VPA is reduced from 15 to 4 hours with concurrent carbapenem administration. It appears that all of the available carbapenems can cause VPA concentrations to decline. Imipenem appears to demonstrate the least effect on VPA, although it clearly can cause a loss of VPA efficacy.

In several studies, patients were noted to have developed increased seizure frequency during carbapenem administration. Although carbapenems have been noted to cause seizures, an acute reduction in the VPA concentration has been associated with status epilepticus and may precipitate seizures in these patients. The carbapenems are eliminated by the kidneys, and this interaction may be more likely to occur in patients with renal dysfunction. Following the discontinuation of the carbapenem, the effect on VPA has been noted to continue for 7 to 14 days. The likely explanation of this prolonged duration of the interaction despite the short half-life of the carbapenems is because of an irreversible inhibition of acylpeptide hydrolase by the carbapenem, resulting in a half-life for recovery of deconjugation estimated to be almost 2 days.

 In nearly all of the reports of this interaction, increasing the dose of VPA did not result in therapeutic VPA concentrations while the carbapenems were coadministered.

The effect of a carbapenem on VPA is significant and may result in reduced efficacy and increased seizure activity. Because of the mechanism of this interaction, increasing the dose of the VPA will unlikely achieve therapeutic plasma concentrations. If possible, an alternative antibiotic should be chosen for patients stabilized on VPA. When a carbapenem is required, additional antiepileptic therapy would be appropriate during carbapenem coadministration and for 1 to 2 weeks after the antibiotic is discontinued.

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Ishikawa T, Otaki H, Mizuta S, et al. Computational study of the competitive binding of valproic acid glucuronide and carbapenem antibiotics to acylpeptide hydrolase. 

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The combined use of valproic acid and a carbapenem is likely to occur in patients with central nervous system infections resulting from head trauma or surgical procedures; serious systemic infections, including pneumonia; and generalized seizure disorders.
 

Valproic Acid and Carbapenem Antibiotics Interaction

The antibacterial agent linezolid is a nonselective inhibitor of monoamine oxidase (MAO), and when it is combined with serotonergic agents, it has been associated with serotonin syndrome. A recent case of serotonin syndrome was reported with concurrent use of linezolid and methadone. 

A 39-year-old man on darunavir, lamivudine, methadone, ritonavir, and tenofovir was admitted with a high fever and septicemia.

 After initial antibiotic therapy with amoxicillin and ceftriaxone, he was switched to 600 mg of clindamycin 4 times a day and 600 mg of linezolid twice a day. Within 3 days he became agitated, confused, and disoriented, and he developed increased tone in both legs, hyperreflexia, and clonus. These symptoms clearly warrant a diagnosis of serotonin syndrome using the more specific Hunter criteria.

 Assessing the causality of the serotonin syndrome because of linezolid plus methadone in this case using the Drug Interaction Probability Scale gives a rating of “probable.”

Methadone is one of the opioids that is known to have serotonergic effects, along with fentanyl, meperidine, and tapentadol. In the case described above, the methadone plasma concentrations may have been higher than expected because 2 of methadone’s metabolic pathways are inhibited by ritonavir (CYP2D6 and CYP3A4) and darunavir (CYP3A4).

Linezolid is a relatively weak nonselective MAO inhibitor, but a number of cases of serotonin syndrome have been reported when it has been combined with serotonergic agents. Most of the case reports have involved the use of linezolid with serotonin-norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), though isolated cases have been reported when linezolid was used with other serotonergic drugs.

Results from retrospective studies suggest that there is a low overall risk of serotonin syndrome in large populations of people receiving linezolid with SNRIs or SSRIs,

 and in many of the reported cases, the patients had a variety of predisposing factors that probably increased their risk.

In one case, a 98-year-old man developed serotonin syndrome after the concurrent use of linezolid with both amiodarone and citalopram.

 The citalopram serum concentrations were probably higher than normal because amiodarone inhibits several of the metabolic pathways and transporters for citalopram such as CYP2D6, CYP3A4, and P-glycoprotein.

In another case, a 68-year-old woman who developed well-documented serotonin syndrome while on linezolid had received 2 serotonergic drugs, fentanyl and amitriptyline.

 Although amitriptyline does not have strong serotonergic effects, it probably added to the serotonergic effects of fentanyl in this case. Other cases of linezolid-associated serotonin syndrome have involved the combined use of fentanyl and fluoxetine in a 4-year-old girl

 and duloxetine and fentanyl in a 55-year-old woman.

A 58-year-old man with obsessive-compulsive disorder was taking 60 mg of fluoxetine a day for 10 years, 100 mg of sertraline for a day for 7 weeks, and 100 mg of fluvoxamine a day for 5 weeks without evidence of serotonin syndrome.

 Fentanyl and linezolid were added, and his SSRIs were stopped. But he developed signs of serotonin syndrome with spontaneous clonus, hyperreflexia, rigidity, and diaphoresis. He responded to discontinuation of the fentanyl and linezolid, along with the serotonin antagonist cyproheptadine, with a 12-mg loading dose, followed by 2 mg every 2 hours. Cyproheptadine has been recommended by others for the prophylaxis or treatment of serotonin syndrome.

Many cases of serotonin syndrome have been reported in patients receiving linezolid, along with serotonergic drugs. Many of the patients had predisposing factors, such as more than 1 serotonergic drug or the presence of other drugs that increase the plasma concentration of the serotonergic drug. Although results from retrospective studies suggest a low prevalence of serotonin syndrome in patients receiving linezolid with serotonergic drugs, those on such therapy should be monitored for evidence of serotonin syndrome. Prompt discontinuation of the serotonergic drugs and the linezolid (if possible) is indicated. Cyproheptadine treatment has apparently been useful in treating serotonin syndrome in several cases, but no controlled studies are available. 

John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD, are professors of pharmacy at the University of Washington School of Pharmacy in Seattle

The antibacterial agent linezolid is a nonselective inhibitor of monoamine oxidase (MAO), and when it is combined with serotonergic agents, it has been associated with serotonin syndrome. A recent case of serotonin syndrome was reported with concur- rent use of linezolid and methadone.

Linezolid and Serotonin Syndrome

Myopathy is a well-established adverse outcome of statin use, and the muscle damage can range from minor muscle pain and weakness to life-threatening rhabdomyolysis. Statin-induced myopathy often occurs and is the result of increased statin plasma concentrations caused by interacting drugs, usually inhibitors of CYP3A4. For some statin drug interactions, other mechanisms may also be involved.

Colchicine can also produce myopathy, and rhabdomyolysis has been reported in severe cases. As with statins, muscle damage often occurs when CYP3A4 inhibitors cause large increases in colchicine plasma concentrations. Given that both colchicine and statins can cause myopathy individually, health care professionals might expect that the combination of statins and colchicine would increase the risk. Numerous credible case reports published over the past 2 decades do suggest that the combination of colchicine and statins may increase the risk of myopathy compared with either drug alone.

In cases of myopathy in patients receiving colchicine and a statin, muscle weakness was the most common finding, occurring in virtually every case. In some cases, the weakness was so severe that the patient could not even stand up. In about one-third of the cases, muscle weakness was accompanied by muscle pain. Darkening of the urine to a tea-colored hue also sometimes accompanied the physical symptoms. 

The onset of the symptoms usually occurred after 2 to 3 weeks of combined therapy, but in some cases, the patient noticed changes after about a week. Occasionally, there was a latent period of 2 to 3 months or more. This is important to note because clinicians may not have a high index of suspicion about something that occurred months previously. 

A study of statin-induced myopathy found that 40% of the patients received a drug that may have predisposed them to the muscle damage, and colchicine was the second-most-common interacting drug.

A more recent report focusing only on simvastatin drug—drug interactions (DDIs) reported that the combination with colchicine was the second-most-common DDI exposure, after gemfibrozil. 

One remarkable case of fatal rhabdomyolysis involving colchicine and simvastatin is instructive.

A 66-year-old man presented with muscle weakness so severe that he had trouble walking and getting up from a chair. His medications were colchicine 1.2 mg per day, cyclosporine 150 mg per day, mycophenolate 500 mg per day, prednisone 7.5 mg per day, and simvastatin 60 mg per day. His creatine kinase (CK) was 2538, suggesting myopathy, so the colchicine and simvastatin were stopped, but he was then given intravenous methylprednisolone and propofol. He developed severe rhabdomyolysis with a CK of 33,580 and died 5 days after admission. 

shows that he received 5 drugs that can individually cause myopathy (represented by the single arrows) and 5 combinations of drugs that have been associated with myopathy and/or pharmacokinetic DDIs (represented by the double arrows). Although it is impossible to determine which drugs were primarily responsible in this tragic case, the ability of cyclosporine to increase plasma concentrations of colchicine, methylprednisolone, and simvastatin may have played a significant role. 

If it is necessary to give patients colchicine and a sta- tin, use conservative doses of both drugs, if possible. The patient should be advised to immediately report any muscle pain or weakness as well as brownish or darkened urine. The patient is likely to fare better if the myopathy is diagnosed quickly and the drugs are discontinued

John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD, are both professors of pharmacy at the University of Washington School of Pharmacy in Seattle. For an electronic version of this article, including references, visit hanstenandhorn.com.

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