Pharmacy Blog – Dr Vibore

Clinical evidence,mechanism, importance and management

In a randomised,three-period study, 15 healthy subjects were given baclofen 10mg three times daily and tizanidine 4mg three times daily, together and alone, for 7 consecutive doses. None of pharmacokinetic parameters of either drug were changed by more than 30%, a figure calculated to indicate presence of an interaction (See reference number 1). No changes in dosages of either drug are therefore likely to be needed if they are taken concurrently.

1. Shellenberger MK,Groves L, Shah J, Novak GD. A controlled pharmacokinetic evaluation oftizanidine and baclofen at steady state. Drug Metab Dispos (1999) 27, 201–204.

Severe hypocalcaemia occurred in two patients taking sodiumclodronate when they were given netilmicin or amikacin. Theoretically,additive calcium lowering effects could occur with anybisphosphonate aminoglycoside combination.

A 62-year-old woman with multiple myeloma was given sodium clodronate 2.4 g daily for osteolysis and bone pain. After 7 days she developed grand mal seizures,and her serum calcium was found to be 1.72 mmol/L (normal range 2.25 to 2.6 mmol/L). Despite daily calcium infusions her calcium remained low. The authors state that symptomatic hypocalcaemia with clodronate is rare, and attributed dramatic response in this patient to an interaction with a course of netilmicin given 5 days earlier for septicaemia (See reference number 1).

A 69-year-old man with prostate cancer had been taking sodium clodronate 2.4 g daily for bone pain for 13 months,and serum calcium levels had always remained within normal limits. After being admitted with febrile neutropenia following a course of chemotherapy, clodronate was withdrawn and he was given intravenous amikacin and ceftazidime. After 7 days he became unconscious,and developed spontaneous twitching movements in his arms and legs. His calcium was found to be

1.39 mmol/L and he was diagnosed with hypocalcaemic tetany. He was given calcium infusions, and his serum calcium returned to normal over next 12 hrs (See reference number 2).

Not fully understood, but one suggestion is that any fall in blood calcium levels brought about by use of clodronate is normally balanced to some extent by excretion of parathyroid hormone, which raises blood calcium levels. However, aminoglycoside antibacterials can damage kidneys, not only causing loss of calcium, but of magnesium as well.

Any hypomagnesaemia inhibits activity of parathyroid gland, so that normal homoeostatic response to hypocalcaemia is reduced or even abolished (See reference number 1,2). Clodronate itself can sometimes be nephrotoxic.

Direct information seems to be limited to these two reports. Biochemical hypocalcaemia is believed to occur in about 10 % of patients taking bisphosphonates,(See reference number 3) but symptomatic hypocalcaemia is said to be rare (See reference number 2). It seems therefore that addition of aminoglycoside in these two cases precipitated severe clinical hypocalcaemia. The authors of both reports therefore advise care if bisphosphonates are given with aminoglycosides,and recommend close monitoring of calcium and magnesium levels. They also point out that renal loss of calcium and magnesium can continue for weeks after aminoglycosides are stopped, and that bisphosphonates can also persist in bone for weeks (See reference number 1,2). This means that interaction is potentially possible whether drugs are given concurrently or sequentially.

Pedersen-Bjergaard U,Myhre J. Severe hypoglycaemia (sic) after treatment with diphosphonate and aminoglycoside. BMJ (1991) 302, 295.

Mayordomo JI,Rivera F. Severe hypocalcaemia after treatment with oral clodronate andaminoglycoside. Ann Oncol (1993) 4, 432–5.

Jodrell DI,Iveson TJ, Smith IE. Symptomatic hypocalcaemia after treatment with high-doseaminohydroxypropylidene diphosphonate. Lancet (1987) i, 622.

The plasma levels of amitriptyline can be reduced by St John’swort, but clinical importance of this interaction is unknown.

Twelve depressed patients were given 75mg of amitriptyline twice daily and 900mg of St John’s wort extract (Lichtwer Pharma,Berlin) daily for at least 14 days. The AUC0-12 of amitriptyline was reduced by about 22 % and AUC of nortriptyline (its metabolite) was reduced by about 41 % (See reference number 1).

Not fully understood, but there is evidence that St John’s wort is an enzyme inducer, which can increase liver metabolism by cytochrome P450 isoenzymes, thereby reducing plasma levels of both amitriptyline and its metabolite (nortriptyline). Induction of P-glycoprotein by St John’s wort may also contribute.

The interaction appears to be established,but its clinical importance is uncertain. Both tricyclics and St John’s wort are antidepressants, but whether final sum of this interaction is more or less antidepressant activity is not known. It was not assessed in this study (See reference number 1). Other tricyclics probably interact similarly because they too can be affected by enzyme-inducing drugs. Monitor for antidepressant efficacy and increased adverse effects if St John’s wort is given with any tricyclic. More study is needed.

1. Johne A,Schmider J, Brockmöller J, Stadelmann AM, Störmer E, Bauer S, Scholler G, Langheinrich M, Roots I. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John’s wort (Hypericum perforatum). J Clin Psychopharmacol (2002) 22, 46–54.

Troleandomycin increases plasma levels of imipramine, andan isolated report suggests that josamycin may possibly increaseamitriptyline serum levels. Erythromycin may possibly raise clomipramine levels,but was not found to interact with other tricyclic antidepressants in one study.

Clinical evidence,mechanism, importance and management

Erythromycin 250mg four times daily for 6 days was found not to affect tricyclic antidepressant levels of 8 patients taking desipramine, imipramine, doxepin, or nortriptyline (See reference number 1). Behavioural changes have been reported in a 15-year-old patient when erythromycin was added to a regimen of clomipramine and risperidone,(See reference number 2) resulting in symptoms compatible with serotonin syndrome, although mental confusion and autonomic instability were absent (See reference number 3). It was suggested that erythromycin increased clomipramine levels by inhibiting its metabolism by cytochrome P450 isoenzyme CYP3A4 (See reference number 4). Clomipramine levels may also have been raised by competition with risperidone for metabolism by CYP2D6.

A patient taking amitriptyline had a marked increase in total serum levels of amitriptyline and its metabolite, nortriptyline, after taking josamycin but no toxicity was reported. It was suggested that josamycin had inhibited amitriptyline metabolism (See reference number 5). This is only an isolated case and its general significance is unknown.

A study in 9 healthy Chinese men found that when they were given troleandomycin 250mg daily for 2 days before a single 100mg oral dose of imipramine, AUC of imipramine was increased by 59 % and its oral clearance was reduced by 30%. It is thought that troleandomycin inhibits N-demethylation of imipramine by inhibiting cytochrome P450 isoenzyme subfamily CYP3A (See reference number 6). The clinical importance of this interaction is uncertain,but it may be prudent to be alert for increased antimuscarinic adverse effects (e.g. dry mouth,blurred vision, urinary retention).

Amsterdam JD,Maislin G. Effect of erythromycin on tricyclic antidepressant metabolism. J Clin Psychopharmacol (1991) 11, 203–6.

Fisman S,Reniers D, Diaz P. Erythromycin interaction with risperidone or clomipramine in anadolescent. J Child Adolesc Psychopharmacol (1996) 6, 133–8.

Fisman S,Diaz P. Erythromycin and clomipramine: Noncompetitive inhibition of demethylation. Reply. J Child Adolesc Psychopharmacol (1996) 6, 213.

Oesterheld JR. Erythromycin and clomipramine: Noncompetitive inhibition of demethylation.J Child Adolesc Psychopharmacol (1996) 6,211–12.

Sánchez Romero A,Calzado Solaz C. Posible interacción entre josamicina y amitriptilina. Med Clin (Barc) (1992) 98, 279.

Wang J-S,Wang W, Xie H-G, Huang S-L, Zhou H-H. Effect of troleandomycin on the pharmacokinetics of imipramine in Chinese: the role of CYP3A. Br J Clin Pharmacol (1997) 44, 195–8.

Concurrent use is not uncommon and normally appears to beuneventful. However,three patients became drowsy, forgetfuland appeared uncoordinated and drunk while taking amitriptyline and chlordiazepoxide. A combined preparation of amitriptyline and chlordiazepoxide (Limbitrol) is available but its advantages have been questioned: adverse effects have been seenin four patients. Diazepam may increase risks of carrying outcomplex tasks (e.g. driving) if added to amitriptyline,as may other combinations of benzodiazepines and tricyclics.

Chlordiazepoxide. Clinical studies in large numbers of patients have shown that incidence of adverse reactions while taking amitriptyline and chlordiazepoxide was no greater than might have been expected with either of drugs used alone,(See reference number 1-3) but a few adverse reports have been documented. A depressed patient taking amitriptyline 150mg and chlordiazepoxide 40mg daily became confused,forgetful and uncoordinated. He acted as though he was drunk (See reference number 4). Two other patients taking amitriptyline and chlordiazepoxide experienced drowsiness, memory impairment, slurring of speech and an inability to concentrate. Both were unable to work and one described himself as feeling drunk (See reference number 5). Four patients taking Limbitrol are reported to have experienced some manifestations of toxicity (delusions,confusion, agitation, disorientation, dry mouth, blurred vi-sion) (See reference number 6). Some of these effects seem to arise from increased CNS depression (possibly additive) and/or an increase in antimuscarinic adverse effects of tricyclic.

Diazepam. A study demonstrated an increase in amitriptyline levels when diazepam was given,(See reference number 7) and two others found that addition of diazepam to amitriptyline 50 to 75mg further reduced attention and performance of a number of psychomotor tests (See reference number 8,9). In contrast,two studies suggested that diazepam did not affect amitriptyline levels (See reference number 3,10).

Studies on effects of nitrazepam and oxazepam on steady-state plasma levels of amitriptyline;(See reference number 3)did not find any interactions

An in vitro study in human liver microsomes found that alprazolam does not affect metabolism (hydroxylation) of desipramine (See reference number 12)

tients taking imipramine, and does not reduce effects of antidepressant.16,17

Zaleplon. A single 75mg dose of imipramine had no effect on pharmacokinetics of zaleplon 20 mg, and psychomotor tests showed only short term additive effects lasting 1 to 2 hrs (See reference number 18).

Zolpidem. A single-dose study using zolpidem 20mg and imipramine 75mg found no effect on pharmacokinetics of either drug. However, imipramine increased sedative effects of zolpidem, and anterograde amnesia was seen (See reference number 19).

Lorazepam may be useful for anxiety or insomnia in elderly depressed patients without impairing response to treatment with nortriptyline (See reference number 20)

Studies on effects of alprazolam, chlordiazepoxide, diazepam, nitrazepam and oxazepam on steady-state plasma levels of nortriptyline(See reference number 3,12,21)found no interactions.

In a study in 10 healthy subjects, when zopiclone and trimipramine were given concurrently for a week, bioavailability of zopiclone was reduced by almost 14 % and bioavailability of trimipramine by almost 27%, but neither of these changes were statistically significant (See reference number 22).

There seems to be no reason for avoiding concurrent use of benzodiazepines and tricyclics although advantages and disadvantages remain subject of debate. Other combinations of tricyclic antidepressants and benzodiazepines would not be expected to behave differently from those described here. Some patients will possibly experience increased drowsiness and inattention with more sedative antidepressants such as amitriptyline, particularly during first few days, and this may be exaggerated by benzodiazepines such as diazepam. Driving risks may therefore be increased.

Haider I. A comparative trial of Ro4–6270 and amitriptyline in depressive illness. Br J Psychiatry (1967) 113,993–8.

General Practitioner Clinical Trials. Chlordiazepoxide with amitriptyline in neurotic depression. Practitioner (1969) 202,437–40.

Silverman G,Braithwaite RA. Benzodiazepines and tricyclic antidepressant plasma levels.BMJ (1973) 3, 18–20.

Kane FJ,Taylor TW. A toxic reaction to combined Elavil-Librium therapy. Am J Psychiatry (1963) 119, 1179–80.

Abdou FA. Elavil-Librium combination. Am J Psychiatry (1964) 120,1204.

Beresford TP,Feinsilver DL, Hall RCW. Adverse reactions to a benzodiazepine-tricyclicantidepressant compound. J Clin Psychopharmacol (1981) 1, 392–4.

Dugal R,Caille G, Albert J-M, Cooper SF. Apparent pharmacokinetic interaction of diazepam and amitriptyline in psychiatric patients: a pilot study. Curr Ther Res (1975) 18, 679–

87.

Patat A,Klein MJ, Hucher M, Granier J. Acute effects of amitriptyline on human performance and interactions with diazepam. Eur J Clin Pharmacol (1988) 35, 585–92.

Moskowitz H,Burns M. The effects on performance of two antidepressants, alone and incombination with diazepam. Prog Neuropsychopharmacol Biol Psychiatry (1988) 12, 783–

92.

Otani K,Nordin C, Bertilsson L. No interaction of diazepam on amitriptyline disposition indepressed patients. Ther Drug Monit (1987) 9, 120–2.

Carson SW,Wright CE, Millikin SP, Lyon J, Chambers JH. Pharmacokinetic evaluation ofthe combined administration of alprazolam and clomipramine. Clin Pharmacol Ther (1992) 51, 154.

Bertilsson L,Åberg-Wistedt A, Lidén A, Otani K, Spina E. Alprazolam does not inhibit themetabolism of nortriptyline in depressed patients or inhibit the metabolism of desipramine inhuman liver microsomes. Ther Drug Monit (1988) 10, 231–3.

Deicken RF. Clonazepam-induced reduction in serum desipramine concentration. J Clin Psychopharmacol (1988) 8,71–3.

Elko CJ,Burgess JL, Robertson WO. Zolpidem-associated hallucinations and serotonin re-uptake inhibition: a possible interaction. Clin Toxicol (1998) 36, 195–203.

Grasela TH,Antal EJ, Ereshefsky L, Wells BG, Evans RL, Smith RB. An evaluation of population pharmacokinetics in therapeutic trials. Part II. Detection of a drug-drug interaction.Clin Pharmacol Ther (1987) 42, 433–41.

Cohn JB. Triazolam treatment of insomnia in depressed patients taking tricyclics. J Clin Psychiatry (1983) 44,401–6.

Dominguez RA,Jacobson AF, Goldstein BJ, Steinbook RM. Comparison of triazolam andplacebo in the treatment of insomnia in depressed patients. Curr Ther Res (1984) 36, 856–65.

Darwish M. Overview of drug interaction studies with zaleplon. Poster presented at 13(See reference number th) Annual Meeting of Associated Professional Sleep Studies (APSS),Orlando, Florida, June 23(See reference number rd), 1999.

Sauvanet JP,Langer SZ, Morselli PL, eds. Imidazopyridines in Sleep Disorders. New York:Raven Press; 1988 p. 165–73.

Buysse DJ,Reynolds CF, Houck PR, Perel JM, Frank E, Begley AE, Mazumdar S, KupferDJ. Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy?J Clin Psychiatry (1997) 58, 426–432.

Gram LF,Overo KF and Kirk L. Influence of neuroleptics and benzodiazepines on metabolism of tricyclic antidepressants in man. Am J Psychiatry (1974) 131, 863.

Caille G,Du Souich P, Spenard J, Lacasse Y, Vezina M. Pharmacokinetic and clinical parameters of zopiclone and trimipramine when administered simultaneously to volunteers. Biopharm Drug Dispos (1984) 5, 117–25.

Colestyramine causes a moderate fall in plasma levels ofimipramine. In vitro evidence suggests that amitriptyline,desipramine and nortriptyline are likely to be similarly affected. Onepatient who had an unusual gut pathology and depression controlled by doxepin became depressed again when colestyraminewas added.

Six depressed patients taking imipramine 75 to 150 mg,usually twice daily, were given colestyramine 4 g three times daily for 5 days. The plasma levels of imipramine fell by an average of 23 % (range 11 to 30%) and plasma levels of desipramine (the major metabolite) fell, although this was less consistent and said not to be statistically significant.

The effect of these reduced levels on control of depression was not assessed (See reference number 1)

A man whose depression was controlled with doxepin relapsed within a week of starting to take colestyramine 6 g twice daily. Within 3 weeks of increasing dosage separation of two drugs from 4 to 6 hrs his combined serum antidepressant levels (i.e. doxepin plus n-desmethyldoxepin) had risen from 39 to 81 nanograms/mL and his depression had improved. Reducing colestyramine dosage to a single 6-g dose daily, separated from doxepin by 15 hours, resulted in a further rise in his serum antidepressant levels to 117 nanograms/mL accompanied by relief of his depression (See reference number 2).

It seems almost certain that these tricyclics become bound to colestyramine (an anion-exchange resin) within gut, thereby reducing their absorption. An in vitro study(See reference number 3) with simulated gastric fluid found that,at pH 1, amitriptyline, desipramine, doxepin, imipramine and nortriptyline were approximately 79 to 90 % bound by colestyramine: at pH 4 they were 36 to 48 % bound and at pH 6.5 they were 62 to 76 % bound. In an earlier study,(See reference number 4)binding of these tricyclics at pH 1 had ranged from 76 to 100%.

The interaction between imipramine and colestyramine is established but of uncertain clinical importance because fall in plasma imipramine levels quoted above was only moderate (23%) and effects were not measured. The single case involving doxepin(See reference number 2) was unusual because patient had an abnormal gastrointestinal tract (hemigastrectomy with pyloroplasty and chronic diarrhoea). Nevertheless it would now be prudent to be alert for any evidence of a reduced antidepressant response if colestyramine is given concurrently. A simple way of minimising admixture of drugs in gut is to separate their administration. It is usually suggested that these drugs should be given 1 hour before or 4 to 6 hrs after colestyramine. There seems to be no direct clinical information about other tricyclics but in vitro studies suggest that amitriptyline,desipramine and nortriptyline probably interact like imipramine.

Spina E,Avenoso A, Campo GM, Caputi AP, Perucca E. Decreased plasma concentrations of imipramine and desipramine following cholestyramine intake in depressed patients. Ther Drug Monit (1994) 16, 432–4.

Geeze DS,Wise MG, Stigelman WH. Doxepin-cholestyramine interaction. Psychosomatics (1988) 29, 233–6.

Bailey DN. Effect of pH changes and ethanol on the binding of tricyclic antidepressants to cholestyramine in simulated gastric fluid. Ther Drug Monit (1992) 14,343–6.

Bailey DN,Coffee JJ, Anderson B, Manoguerra AS. Interactions of tricyclic antidepressants with cholestyramine in vitro. Ther Drug Monit (1992) 14, 339–42.

Clinical evidence,mechanism, importance and management

A 21-year-old woman taking nortriptyline 30mg daily experienced marked tachycardia (an increase from 90 to 160 bpm) after smoking a cannabis cigarette. It was controlled with propranolol (See reference number 1). A 26-year-old complained of restlessness,dizziness and tachycardia (120 bpm) after smoking cannabis while taking imipramine 50mg daily (See reference number 2). Four adolescents aged 15 to 18 taking tricyclic antidepressants for attention-deficit hyperactivity disorder had transient cognitive changes,delirium and tachycardia after smoking cannabis (See reference number 3).

Increased heart rates are well-documented adverse effects of both tricyclic antidepressants and cannabis, and what occurred was probably due to additive beta-adrenergic and antimuscarinic effects of tricyclics, with beta-adrenergic effect of cannabis. Direct information is limited but it has been suggested that concurrent use should be avoided (See reference number 1).

Hillard JR,Vieweg WVR. Marked sinus tachycardia resulting from the synergistic effects ofmarijuana and nortriptyline. Am J Psychiatry (1983) 140, 626–7.

Kizer KW. Possible interaction of TCA and marijuana. Ann Emerg Med (1980) 9,444.

Wilens TE,Biederman J, Spencer TJ. Case study: adverse effects of smoking marijuana whilereceiving tricyclic antidepressants. J Am Acad Child Adolesc Psychiatry (1997) 36, 45–8.

Ketoconazole or itraconazole may inhibit metabolism of trazodone

Clinical evidence,mechanism, importance and management

An in vitro study demonstrated that ketoconazole inhibited metabolism of trazodone to its principal metabolite, meta-chlorophenylpiperazine (See reference number 1). Trazodone is a substrate for cytochrome P450 isoenzyme CYP3A4 and inhibitors of this enzyme such as ketoconazole or itraconazole may inhibit its metabolism, leading to substantial increases in trazodone plasma concentrations with potential for adverse effects (See reference number 2-4). The FDA in US and manufacturers of trazodone recommend that a lower dose of trazodone should be considered if it is given with a potent CYP3A4 inhibitor such as ketoconazole or itraconazole (See reference number 2-4). However, UK manufacturer also suggests that combination should be avoided where possible (See reference number 4).

Zalma A,von Moltke LL, Granda BW, Harmatz JS, Shader RI, Greenblatt DJ. In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and human immunodeficiency viralprotease inhibitors. Biol Psychiatry (2000) 47, 655–61.

Desyrel (Trazodone hydrochloride). Bristol-Myers Squibb Company. US Prescribing information,January 2005.

Lewis-Hall FC. Bristol-Myers Squibb Company. Letter to healthcare professionals,April 2004.

Molipaxin (Trazodone hydrochloride). Sanofi-Aventis. UK Summary of product characteristics,July 2005.

Limited evidence suggests that effects of fluoxetine are increased by aminoglutethimide

Clinical evidence,mechanism, importance and management

A patient with severe obsessive-compulsive disorder,resistant to clomipramine combined with SSRIs, improved when given fluoxetine 40mg daily and aminoglutethimide 250mg four times daily. Over a four-and-ahalf year period, whenever attempts were made to reduce dosage of either drug, patient started to relapse (See reference number 1). Thus at least one patient has taken both drugs together without problems, and evidence suggests that aminoglutethimide has a potentiating effect on fluoxetine. However, more study is needed to confirm efficacy and safety of this drug combination in other patients.

1. Chouinard G,Bélanger M-C, Beauclair L, Sultan S, Murphy BEP. Potentiation of fluoxetineby aminoglutethimide, an adrenal steroid suppressant, in obsessive-compulsive disorder resistant to SSRIs: a case report. Prog Neuropsychopharmacol Biol Psychiatry (1996) 20, 1067–79.

Fluoxetine modestly raised levels of ritonavir, and ritonavir ispredicted to raise levels of fluoxetine, paroxetine and sertraline. Afew cases of serotonin syndrome have been attributed to theuse of fluoxetine and ritonavir. The concurrent use of escitalopram and ritonavir do not appear to affect pharmacokineticsof either drug.

Clinical evidence,mechanism, importance and management

In a single-dose study involving 18 healthy subjects,no significant pharmacokinetic interaction was seen when ritonavir was given with escitalopram (See reference number 1).

Ritonavir 600mg was given to 16 healthy subjects before and after 8 days of treatment with fluoxetine 30mg twice daily. The maximum plasma levels of ritonavir were unaffected,but its AUC rose by 19%. These changes were not considered large enough to warrant changing dose of ritonavir (See reference number 2). The study was criticised for not achieving steady state before assessing pharmacokinetics and thus possibly underestimating interaction (See reference number 3). However, authors point out that fluoxetine levels were equivalent to those seen at steady state, and multiple dosing of ritonavir is likely to induce its own metabolism, so if anything, interaction would be lessened at steady state (See reference number 4).

The UK manufacturers of ritonavir predict that it may raise levels of SSRIs (fluoxetine, paroxetine, sertraline) due to inhibitory effect of ritonavir on cytochrome P450 isoenzymes CYP2D6 (See reference number 5). The US manufacturers do not mention any specific SSRIs (See reference number 6). Both manufacturers suggest careful monitoring of adverse effects when these drugs are used with ritonavir; a dose reduction of SSRI may be required (See reference number 5,6).

Two cases of serotonin syndrome were attributed to adding ritonavir to established fluoxetine treatment. In one patient this was managed by halving fluoxetine dose, and in other ritonavir was withdrawn. Other cases of serotonin syndrome have been seen in patients taking ritonavir or indinavir with fluoxetine. One involved additional use of trazodone, , and other involved large quantities of grapefruit, .

Gutierrez,MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther (2003) 25, 1200–10.

Ouellet D,Hsu A, Qian J, Lamm JE, Cavanaugh JH, Leonard JM, Granneman GR. Effect offluoxetine on the pharmacokinetics of ritonavir. Antimicrob Agents Chemother (1998) 42, 3107–12.

Bellibas SE. Ritonavir-fluoxetine interaction. Antimicrob Agents Chemother (1999) 43,1815.

Ouellet D,Hsu A. Ritonavir-fluoxetine interaction. Antimicrob Agents Chemother (1999) 43, 1815.

Norvir (Ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,May2007.

Norvir (Ritonavir). Abbott Laboratories. US Prescribing information,January 2006.