Pharmacy Blog – Dr Vibore

The concurrent use of lithium and tetracyclines is normallyuneventful, but two isolated reports describe increased serum-lithium levels and lithium toxicity, one in a woman taking tetracycline, and other in a man taking doxycycline. An isolated caseof pseudotumor cerebri occurred in one patient taking lithiumand minocycline.

A man on long-term treatment with lithium carbonate became confused within a day of starting to take doxycycline 100mg twice daily. By end of a week he had developed symptoms of lithium toxicity (ataxia, dysarthria, worsened tremor, fatigue, etc.). His serum-lithium levels had risen from a range of 0.8 to 1.1 mmol/L up to 1.8 mmol/L; his renal function remained normal. He recovered when doxycycline was withdrawn (See reference number 1).

A case report describes pseudotumor cerebri in an obese 15-year-old girl taking lithium,4 months after she started taking minocycline 75mg twice daily for acne (See reference number 2).

An isolated report describes a woman, who had been taking lithium for 3 years, with serum levels within range of 0.5 to 0.84 mmol/L. Within 2 days of starting to take a sustained-release form of tetracycline (Tetrabid) her serum-lithium levels had risen to 1.7 mmol/L,and 2 days later they had further risen to 2.74 mmol/L. By then she showed clear symptoms of lithium toxicity (slight drowsiness, slurring of speech, fine tremor and thirst) (See reference number 3).

In contrast,13 healthy subjects taking lithium carbonate 450mg twice daily or 900mg once daily had a small reduction in serum-lithium levels (from 0.51 to 0.47 mmol/L) when they were given tetracycline 500mg twice daily for 7 days (See reference number 4). The incidence of adverse reactions remained largely unchanged,except for a slight increase in CNS and gastrointestinal adverse effects.

One suggested reason for increased serum-lithium levels is that tetracycline (known to have nephrotoxic potential) may have adversely affected renal clearance of lithium (See reference number 3)

These adverse interaction reports are isolated and unexplained. Two reports make point that these drugs are commonly used for acne caused by lithium,(See reference number 1,5) so any common interaction resulting in raised lithium levels would be expected to have come to light by now. The case of pseudotumor cerebri also appears rare, but note that female gender and obesity are risk factors for its development and so greater caution may be warranted in this type of patient (See reference number 2). The authors advise frequent enquiry about headaches and visual changes.

There would seem to be no reason for avoiding concurrent use of lithium and tetracycline, doxycycline or minocycline, but be aware of potential for a rare interaction. Consider also Lithium + Antibacterials interaction.

Miller SC. Doxycycline-induced lithium toxicity. J Clin Psychopharmacol (1997) 17,54–5.

Jonnalagadda J,Saito E, Kafantaris V. Lithium, minocycline, and pseudotumor cerebri. J Am Acad Child Adolesc Psychiatry (2005) 44, 209.

McGennis AJ. Lithium carbonate and tetracycline interaction. BMJ (1978) 2,1183.

Fankhauser MP,Lindon JL, Connolly B, Healey WJ. Evaluation of lithium–tetracycline interaction. Clin Pharm (1988) 7, 314–17.

Jefferson JW. Lithium and tetracycline. Br J Dermatol (1982) 107,370.

Clinical evidence,mechanism, importance and management

In a randomised,double-blind, crossover study, 12 healthy subjects were given lithium carbonate 600mg daily or placebo for 10 days, with a single 30mg dose of mirtazapine on day 10. The pharmacokinetics of both mirtazapine and lithium were unaltered by concurrent use. In addition,no pharmacodynamic changes, as studied by psychometric testing, were identified (See reference number 1).

1. Sitsen JMA,Voortman G, Timmer CJ. Pharmacokinetics of mirtazapine and lithium in healthymale subjects. J Psychopharmacol (2000) 14, 172–6.

There is some evidence that excretion of lithium can be increased by short-term use of acetazolamide. However, lithium toxicity has been seen in one patient given combination for a month.

Clinical evidence,mechanism, importance and management

A single-dose study in 6 subjects given lithium 600mg ten hrs before acetazolamide 500 or 750mg found a 31 % increase in urinary excretion of lithium (See reference number 1). A woman was successfully treated for a lithium overdose with acetazolamide,intravenous fluids, sodium bicarbonate, potassium chloride and mannitol (See reference number 2).

Paradoxically,lithium toxicity occurred in another patient after a month of treatment with acetazolamide. Lithium levels rose from 0.8 to 5 mmol/L, although it should be noted that later measurement was taken 8 hrs post-dose (See reference number 3). See Lithium, for details of lithium monitoring.

Thomsen K,Schou M. Renal lithium excretion in man. Am J Physiol (1968) 215, 823–7.

Horowitz LC,Fisher GU. Acute lithium toxicity. N Engl J Med (1969) 281, 1369.

Gay C,Plas J, Granger B, Olie JP, Loo H. Intoxication au lithium. Deux interactions inédites:l’acétazolamide et l’acide niflumique. Encephale (1985) 11, 261–2.

Clinical evidence,mechanism, importance and management

A 42-year-old woman,taking lithium carbonate 450mg twice daily, developed signs of lithium toxicity 6 days after starting treatment with intravenous aciclovir 10 mg/kg, which was given every 8 hrs for a severe herpes zoster infection following chemotherapy. Her serum-lithium levels had risen over fourfold to 3.4 mmol/L. The reasons for this interaction are unknown but authors of report postulate that aciclovir may have inhibited renal excretion of lithium (See reference number 1).

This appears to be first and only report of this interaction, but it would now be prudent to monitor for symptoms of lithium toxicity (see Lithium, ) and consider monitoring lithium levels if high-dose intravenous aciclovir is given to any patient. The report recommends measuring lithium levels every second or third day (See reference number 1). Oral aciclovir is predicted not to interact because of its low bioavailability, and no interaction would be expected with topical aciclovir as plasma levels achieved by this route are minimal.

1. Sylvester RK,Leitch J, Granum C. Does acyclovir increase serum lithium levels? Pharmacotherapy (1996) 16, 466–8.

No clinically relevant interaction has been seen between orlistatand atorvastatin,pravastatin or simvastatin.

Clinical evidence,mechanism, importance and management

In a randomised study,32 healthy subjects were given atorvastatin 20mg daily for 6 days, with or without orlistat 120mg three times daily for 6 days. Orlistat had no significant effect on pharmacokinetics of atorvastatin (See reference number 1).

In a placebo-controlled, crossover study in 24 subjects with mild hypercholesterolaemia, orlistat 120mg three times daily was reported to have no effect on pharmacokinetics, or lipid-lowering effects, of pravastatin 40mg daily, when both drugs were given for 6 days (See reference number 2).

A review includes brief details of a comparative study in two groups of healthy subjects given pravastatin,either with orlistat or placebo. After 10 days there was no significant difference in pravastatin AUC between groups, but maximum serum concentration did show a tendency to be higher in orlistat group (See reference number 3).

In a placebo-controlled, randomised study in 29 healthy subjects orlistat 120mg three times daily had no effect on pharmacokinetics of simvastatin 40mg daily (See reference number 4).

Zhi J,Moore R, Kanitra L, Mulligan TE. Pharmacokinetic evaluation of the possible interaction between selected concomitant medications and orlistat at steady state in healthy subjects.J Clin Pharmacol (2002) 42, 1011–19.

Oo CY,Akbari B, Lee S, Nichols G, Hellmann CR. Effect of orlistat, a novel anti-obesityagent, on the pharmacokinetics and pharmacodynamics of pravastatin in patients with mild hypercholesterolaemia. Clin Drug Invest (1999) 17, 217–23.

Guerciolini R. Mode of action of orlistat. Int J Obes (1997) 21 (Suppl 3),S12–S23.

Zhi J,Moore R, Kanitra L, Mulligan TE. Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthyvolunteers. J Clin Pharmacol (2003) 43, 428–34.

Everolimuspharmacokinetics were unaltered by statins

1. Kovarik JM,Hartmann S, Hubert M, Berthier S, Schneider W, Rosenkranz B, Rordorf C. Pharmacokinetic and pharmacodynamic assessments of HMG-CoA reductase inhibitors whencoadministered with everolimus. J Clin Pharmacol (2002) 42, 222–8.

Marked increases in tacrolimus levels and toxicity were observedwhen three patients were also given nefazodone. In theory,fluvoxamine may increase tacrolimus levels. Paroxetine and sertraline may not interact, but situation is not clear.

A kidney transplant patient taking tacrolimus 5mg daily developed delirium and renal failure 4 weeks after starting to take nefazodone 150mg daily. The tacrolimus levels had been 9.4 nanograms/mL some 3 months earlier when he was taking a dose of 6mg daily, but in presence of nefazodone tacrolimus level increased to 46.4 nanograms/mL with a tacrolimus dose of 5mg daily. His serum creatinine had doubled. The tacrolimus level fell to 29.6 nanograms/mL within 2 days of dose being reduced to 3mg daily. Nefazodone was then replaced by paroxetine 20mg daily. After 3 days tacrolimus dose was increased to 5mg daily and satisfactory levels of 12.4 nanograms/mL were observed (See reference number 1).

A kidney transplant patient taking prednisone,azathioprine and tacrolimus 5mg daily for 2 years experienced headache, confusion and grey areas in her vision within one week of starting nefazodone 50mg twice daily in place of sertraline, for depression. Her serum creatinine had risen from 132 to 195 micromol/Land her trough tacrolimus level was greater than 30 nanograms/mL. Nefazodone was replaced by sertraline,and tacrolimus was withheld for 4 days. Signs of tacrolimus-induced neurotoxicity disappeared within 36 hrs and serum creatinine and tacrolimus levels returned to pretreatment levels within 2 weeks (See reference number 2).

Another patient developed raised liver enzymes and raised tacrolimus levels after taking nefazodone and tacrolimus for 2 weeks. When nefazodone was stopped his liver enzymes normalised over next 5 days, and his tacrolimus levels fell from 23 to 9.5 nanograms/mL over 10 days (See reference number 3).

Tacrolimus is metabolised by cytochrome P450 isoenzyme CYP3A4, which is inhibited by nefazodone, concurrent use therefore results in increased levels of tacrolimus. Paroxetine and sertraline do not have significant effects on CYP3A4 and are therefore not expected to interact with tacrolimus.

Information appears to be limited but what is known indicates that tacrolimus levels or at least signs of toxicity should be well monitored if nefazodone is also given. In view of narrow therapeutic index of tacrolimus, it may be advisable to avoid concurrent nefazodone.

Fluvoxamine is an inhibitor of CYP3A4(See reference number 4) and so theoretically could affect metabolism of tacrolimus. Close monitoring of tacrolimus levels is therefore advised. Paroxetine and sertraline and possibly other SSRIs may be suitable alternative antidepressants, but evidence is slim, so additional monitoring may still be warranted (See reference number 1). Further study on use of antidepressants with tacrolimus is needed.

Campo JV,Smith C, Perel JM. Tacrolimus toxic reaction associated with the use of nefazodone: paroxetine as an alternative agent. Arch Gen Psychiatry (1998) 55, 1050–2.

Olyaei AJ,deMattos AM, Norman DJ, Bennett WM. Interaction between tacrolimus and nefazodone in a stable renal transplant recipient. Pharmacotherapy (1998) 18, 1356–9.

Garton T,Nefazodone and CYP450 3A4 interactions with cyclosporine and tacrolimus. Transplantation (2002) 74, 745.

Faverin (Fluvoxamine). Solvay Healthcare Ltd. UK Summary of product characteristics,June2006.

Clinical evidence,mechanism, importance and management

2.7 nanograms/mL in a kidney transplant patient within 4 days of danazol 400mg to 1.2 g daily being started. Despite a reduction in danazol dosage to 600mg and then 400mg daily, her tacrolimus and creatinine serum levels remained high for one month until danazol was withdrawn. The reason is not known, but authors suggest that danazol possibly inhibits metabolism (demethylation and hydroxylation) of tacrolimus by liver so that it is cleared from body more slowly (See reference number 1). Tacrolimus is metabolised by cytochrome P450 isoenzyme CYP3A4, and danazol has been shown to inhibit this pathway (consider Statins + Danazol interaction). Therefore although this is an isolated case it seems possible that it will be of general significance. Monitor effects of concurrent use in any patient, reducing tacrolimus dosage as necessary.

1. Shapiro R,Venkataramanan R, Warty VS, Scantlebury VP, Rybka W, McCauley J, Fung JJ,Starzl TE. FK 506 interaction with danazol. Lancet (1993) 341, 1344–5.

A retrospective study identified 3 patients taking tacrolimus who had received a total of 5 courses of intravenous chloramphenicol,each lasting for at least 12 days. Tacrolimus trough blood levels were doubled by day 2,and had risen by 207 % at their peak, on day 6. The tacrolimus dose had been decreased by about one-third by day 12, and tacrolimus levels returned to around baseline value (See reference number 1).

An adolescent patient with a kidney transplant developed toxic tacrolimus levels on second day of starting chloramphenicol for a vancomycin-resistant enterococcal infection. The tacrolimus dosage had to be reduced by 83 % to achieve safe serum levels, and it was found that dose-adjusted tacrolimus AUC was 7.5-fold greater in presence of chloramphenicol (See reference number 2). Another report describes a similar interaction in a liver transplant patient taking tacrolimus 4mg twice daily. The patient was given intravenous chloramphenicol, but at unintentionally high dose of 1850mg every 6 hours. After about 3 days patient complained of lethargy, fatigue, headaches and tremors so both drugs were stopped. His tacrolimus trough level had increased from a range of 9 to 11 nanograms/mL to more than 60 nanograms/mL. Seven days after chloramphenicol had been stopped his tacrolimus level was 8.2 nanograms/mL and his symptoms had resolved (See reference number 3). Another case report in a kidney-pancreas transplant patient taking tacrolimus 4mg twice daily found that addition of oral chloramphenicol 750mg four times daily increased tacrolimus trough blood level to more than 30 micrograms/L within 3 days. After 10 days, dose of tacrolimus was reduced to 1.5mg twice daily and tacrolimus level fell to between 18 to 25 micrograms/L. Chloramphenicol was stopped 5 days later and tacrolimus dose was increased to 3mg twice daily. However tacrolimus level fell to below 5 micrograms/L for several days leading to an episode of acute organ rejection. The tacrolimus level then returned to within therapeutic range and patient stabilised (See reference number 4).

These appear to be only reports of this interaction, but it is consistent with known metabolic characteristics of both drugs and therefore it is expected to be an interaction of general importance. Monitor outcome closely if systemic chloramphenicol is given to any patient taking tacrolimus, being alert for need to reduce tacrolimus dosage. It seems doubtful if a clinically relevant interaction will occur with topical chloramphenicol because dosage and systemic absorption is small, but this needs confirmation.

Mathis AS,Shah N, Knipp GT, Friedman GS. Interaction of chloramphenicol and the calcineurin inhibitors in renal transplant recipients. Transpl Infect Dis (2002) 4, 169–74.

Schulman SL,Shaw LM, Jabs K, Leonard MB, Brayman KL. Interaction between tacrolimusand chloramphenicol in a renal transplant recipient. Transplantation (1998) 65, 1397–8.

Taber DJ,Dupuis RE, Hollar KD, Strzalka AL, Johnson MW. Drug-drug interaction betweenchloramphenicol and tacrolimus in a liver transplant recipient. Transplant Proc (2000) 32, 660–62.

Bakri R,Breen C, Maclean D, Taylor J, Goldsmith D. Serious interaction between tacrolimusFK506 and chloramphenicol in a kidney-pancreas transplant recipient. Transpl Int (2003) 16, 441–3.