Levodopa + Beta blockers - Drug Interactions

The concurrent use of levodopa and beta blockers normally appears to be favourable,but be aware that, as with all antihypertensives, additive hypotensive effects can occur.

Clinical evidence,mechanism, importance and management

Most of effects of combined use of levodopa and beta blockers seem to be favourable, although additive hypotension can be a problem. Dopamine derived from levodopa stimulates beta-receptors in heart, which can cause arrhythmias (See reference number 1). These receptors are blocked by propranolol and other beta blockers. An enhancement of effects of levodopa and a reduction in tremor has been described in 23 out of 25 patients taking propranolol,(See reference number 2) but not in 9 patients taking oxprenolol,(See reference number 3) or in another placebo-controlled study in 18 patients taking propranolol (See reference number 4). Early evidence showed that growth hormone levels were substantially raised by propranolol(See reference number 5,6) or practolol(See reference number 6) [now withdrawn due to fatal reactions] in conjunction with levodopa,but no clinical relevance for this has been demonstrated.

Goldberg LI,Whitsett TL. Cardiovascular effects of levodopa. Clin Pharmacol Ther (1971) 12, 376–82.

Kissel P,Tridon P, André JM. Levodopa-propranolol therapy in parkinsonian tremor. Lancet (1974) ii, 403–4.

Sandler M,Fellows LE, Calne DB, Findley LJ. Oxprenolol and levodopa in parkinsonian patients. Lancet (1975) i, 168.

Marsden CD,Parkes JD, Rees JE. Propranolol in Parkinson’s disease. Lancet (1974) ii, 410.

Camanni F,Massara F. Enhancement of levodopa-induced growth-hormone stimulation bypropranolol. Lancet (1974) i, 942.

Lotti G,Delitala G, Masala A. Enhancement of levodopa-induced growth-hormone stimulationby practolol. Lancet (1974) 2, 1329.

Apomorphine + Hormonal contraceptives - Drug Interactions

Clinical evidence,mechanism, importance and management

A study(See reference number 1) in a group of 9 women found that sedative effects of a single 5-micrograms/kg subcutaneous dose of apomorphine were decreased when they were taking a combined oral contraceptive (ethinylestradiol 30 micrograms, levonorgestrel 150 or 250 micrograms). The clinical importance of this is uncertain.

1. Chalmers JS,Fulli-Lemaire I, Cowen PJ. Effects of the contraceptive pill on sedative responsesto clonidine and apomorphine in normal women. Psychol Med (1985) 15, 363–7.

Vinca alkaloids + Azoles - Drug Interactions

Itraconazole can increase toxicity of vincristine and vinblastine; posaconazole and voriconazole may interact similarly. Thereis a theoretical possibility that itraconazole and ketoconazole mayincrease toxicity of vinorelbine

Clinical evidence,mechanism, importance and management

Four out of 14 patients with ALL given induction chemotherapy with weekly injections of vincristine (with prednisone, daunorubicin and asparaginase) and antifungal prophylaxis with itraconazole 400mg daily, developed severe and early vincristine-induced neurotoxicity (paraesthesia and muscle weakness of hands and feet, paralytic ileus, mild laryngeal nerve paralysis). The degree and early onset of these neurotoxic reactions were unusual,and were all reversible except for mild paraesthesia in one patient. The complications were more serious than in a previous series of 460 patients given vincristine without itraconazole (29% compared to 6%).(See reference number 1) Five children with ALL developed severe vincristine toxicity attributed to concurrent use of itraconazole. They were also receiving nifedipine, , which is known to reduce clearance of vincristine, and which may have made things worse.(See reference number 2) Severe vincristine neurotoxicity developed in four other children(See reference number 3-5) and two adults(See reference number 6) with ALL when they were given itraconazole. Another study similarly indicates that greater vincristine toxicity may occur in patients given itraconazole.

The reasons for this interaction are not understood, but among suggestions are that itraconazole inhibits metabolism of vincristine by cytochrome P450 enzyme system, so that it is cleared from body less quickly (See reference number 1). Another possible explanation is that itraconazole inhibits P-glycoprotein,(See reference number 1) and increased vincristine neurotoxicity may be result of inhibition of this pump in endothelial cells of blood-brain barrier (See reference number 7).

The authors of one report(See reference number 1) suggest that itraconazole should be avoided in patients taking vincristine, and manufacturers of vincristine also issue a warning about increased risks of concurrent use (See reference number 8).

Acute neurotoxicity and myelotoxicity occurred in a boy with Hodgkin’s lymphoma treated with vinblastine,doxorubicin and methotrexate when he was also given itraconazole. The toxicity did not occur when he was given same chemotherapy without itraconazole (See reference number 9).

Some UK(See reference number 10) and US(See reference number 11) manufacturers advise caution if vinorelbine, which is metabolised by CYP3A4, is given with inhibitors of this isoenzyme such as itraconazole and ketoconazole because of theoretical risk of increased neurotoxicity. The manufacturers of vindesine note that concurrent administration with CYP3A inhibitors may result in early onset or increased severity of vindesine side-effects (See reference number 12).

The manufacturers of posaconazole advise avoidance of concurrent use with vinca alkaloids (vincristine and vinblastine are named), but if they are given, then dose adjustments of vinca alkaloids should be considered (See reference number 13).

The manufacturers of voriconazole advise caution if it is given to patients treated with vinca alkaloids (vincristine and vinblastine are named) because of risk of neurotoxicity (See reference number 14,15). The US manufacturer recommends that dose adjustments of vinca alkaloids should be considered (See reference number 15)

Böhme A,Ganser A, Hoelzer D. Aggravation of vincristine-induced neurotoxicity by itraconazole in the treatment of adult ALL. Ann Hematol (1995) 71, 311–12.

Murphy JA,Ross LM, Gibson BES. Vincristine toxicity in five children with acute lymphoblastic leukaemia. Lancet (1995) 346, 443.

Ariffin H,Omar KZ, Ang EL, Shekhar K. Severe vincristine neurotoxicity with concomitantuse of itraconazole. J Paediatr Child Health (2003) 39, 638–9.

Jeng MR,Feusner J. Itraconazole-enhanced vincristine neurotoxicity in a child with acutelymphoblastic leukemia. Pediatr Hematol Oncol (2001) 18, 137–42.

Sathiapalan RK,Al-Nasser A, El-Sohl H, Al-Mohsen I, Al-Jumaah S. Vincristine-itraconazole interaction: cause for increasing concern. J Pediatr Hematol Oncol (2002) 24, 591.

Gillies J,Hung KA, Fitzsimons E, Soutar R. Severe vincristine toxicity in combination withitraconazole. Clin Lab Haematol (1998) 20, 123–4.

Muenchow N,Janka G, Erttmann R, Looft G, Bielack S, Winkler K. Increased vincristine neurotoxicity during treatment with itraconazole in 3 pediatric patients with acute myelogenous leukaemia. Blood (1999) 94 (Suppl 1, part 2) 234b.

Vincristine sulphate. Mayne Pharma plc. UK Summary of product characteristics,April2004.

Bashir H,Motl S, Metzger ML, Howard SC, Kaste S, Krasin MP, Hudson MM. Itraconazoleenhanced chemotherapy toxicity in a patient with Hodgkin lymphoma. J Pediatr Hematol Oncol (2006) 28, 33–5.

Vinorelbine. Mayne Pharma plc. UK Summary of product characteristics,June 2006.

Navelbine (Vinorelbine tartrate). Pierre Fabre Pharmaceuticals Inc. US Prescribing information,August 2005.

Eldisine (Vindesine). Eli Lilly and Company Ltd. UK Summary of product characteristics,September 1998.

Noxafil (Posaconazole). Schering-Plough Ltd. UK Summary of product characteristics,October 2006.

VFEND (Voriconazole). Pfizer Ltd. UK Summary of product characteristics,July 2007.

VFEND (Voriconazole). Pfizer Inc. US Prescribing information,November 2006.

Vinca alkaloids; Vincristine + Asparaginase - Drug Interactions

Hildebrand J,Kenis Y. Vincristine neurotoxicity. N Engl J Med (1972) 287, 517.

Hildebrand J,Kenis Y. Additive toxicity of vincristine and other drugs for the peripheral nervous system. Acta Neurol Belg (1971) 71, 486–91.

Vincristine sulphate. Mayne Pharma plc. UK Summary of product characteristics,April 2004.

Antiparkinsonian and related drugs - Drug Interactions

The drugs in this section are considered together because their major therapeutic application is in treatment of Parkinson’s disease, although some of related antimuscarinic (anticholinergic) drugs included here are also used for other conditions. Parkinson’s disease is named after Dr James Parkinson who originally described four main signs of disease, namely rigidity, tremor, dystonias and dyskinesias (movement disorders). Similar symptoms may also be displayed as unwanted adverse effects of therapy with certain drugs.

The basic cause of disease lies in basal ganglia of brain, particularly striatum and substantia nigra, where normal balance between dopaminergic nerve fibres (those that use dopamine as chemical transmitter) and cholinergic nerve fibres (those that use acetylcholine as transmitter) is lost, because dopaminergic fibres degenerate. As a result cholinergic fibres end up in relative excess. Much of treatment of Parkinson’s disease is based on an attempt to redress balance, and there are several groups of drugs that can be used to this end. These are listed in table 1 below,(below), and discussed below.

Levodopa can pass blood-brain barrier (unlike dopamine), where it is converted into dopamine, and thus acts by topping up CNS dopaminergic system. Levodopa is most usually given with carbidopa or benserazide (dopa-decarboxylase inhibitors), which prevent wasteful peripheral metabolism of levodopa. This allows lower doses of levodopa to be given,which results in fewer adverse effects.

These drugs may augment dopaminergic activity in brain

Bromocriptine, cabergoline, pergolide, ropinirole and similar drugs act as dopamine agonists and so also have effect of increasing dopaminergic activity in brain.

The catechol-O-methyltransferase (COMT) inhibitors work by inhibiting peripheral metabolism of levodopa by COMT. Note that this enzyme is major metabolising enzyme for levodopa when a decarboxylase inhibitor (e

The selective irreversible MAO-B inhibitors enhance dopamine activity by preventing dopamine degradation. These drugs sometimes interact like older non-selective MAOIs, and reader is cross-referred to information under MAOIs when appropriate. Selegiline undergoes rapid first-pass metabolism to produce amfetamine metabolites. A buccal tablet has been developed,which markedly reduces this first-pass metabolism, and is consequently given as a smaller dose.

Benzhexol, orphenadrine, procyclidine and other antimuscarinic (anticholinergic) drugs work by correcting relative cholinergic excess.

The interactions that affect antimuscarinic effects of these drugs are discussed in this section. However, antimuscarinics also affect actions of other drugs (such as centrally-acting anticholinesterases) and these are therefore discussed elsewhere in publication.

Entacapone,Tolcapone

Bromocriptine,Cabergoline, Lisuride, Pergolide

Piribedil,Pramipexole, Quinagolide, Ropinirole, Rotigotine

Rasagiline,Selegiline

Benserazide,Carbidopa

Benzatropine,Biperiden, Bornaprine, Dexetimide, Metixene, Orphenadrine, Procyclidine, Profenamine, Trihexyphenidyl, Tropatepine

Table 1 Antiparkinsonian drugs
Group Drugs
Dopaminergic drugs
Amino-acid precursor of dopamine Levodopa
Levodopa combined with a peripheral dopa-decarboxylase inhibitor Co-beneldopa (levodopa + benserazide) Co-careldopa (levodopa + carbidopa)
COMT-inhibitors Entacapone, Tolcapone
Dopamine agonists
Ergot derivatives Bromocriptine, Cabergoline, Lisuride, Pergolide
Non-ergot dopamine agonists Piribedil, Pramipexole, Quinagolide, Ropinirole, Rotigotine
Other dopamine agonists Apomorphine
MAO-B inhibitors Rasagiline, Selegiline
Other Amantadine
Other
Peripheral dopa-decarboxylase inhibitors Benserazide, Carbidopa
Antimuscarinics Benzatropine, Biperiden, Bornaprine, Dexetimide, Metixene, Orphenadrine, Procyclidine, Profenamine, Trihexyphenidyl, Tropatepine

Taxanes; Paclitaxel + Miscellaneous - Drug Interactions

Clinical evidence,mechanism, importance and management

(a) Cimetidine,Dexamethasone, Diphenhydramine

On basis of an in vitro study using human liver slices and human liver microsomes it has been concluded that metabolism of paclitaxel is unlikely to be altered by cimetidine, dexamethasone or diphenhydramine, all of which are frequently given to prevent hypersensitivity reactions associated with paclitaxel or its vehicle, Cremophor (see b, below) (See reference number 1). The UK manufacturers say that paclitaxel clearance in patients is not affected by cimetidine premedication,(See reference number 2) although some authors(See reference number 3) have advised caution when using cimetidine with docetaxel or paclitaxel since cimetidine is known to affect cytochrome P450 isoenzyme CYP3A4, which is responsible, in part, for metabolism of these taxanes.

In vitro, Cremophor was found to inhibit metabolism of paclitaxel in human liver microsomes,(See reference number 1) which might be expected to increase its toxicity. The concentration used in in vitro study may be achieved clinically in patients given paclitaxel with Cremophor as vehicle (See reference number 4). This may be worth bearing in mind if other drugs formulated with Cremophor are given with paclitaxel.

An in vitro study in human bladder cancer cells found that antineoplastic effect of paclitaxel in combination with methotrexate was dependent on order of exposure to two drugs (See reference number 5)

Jamis-Dow CA,Klecker RW, Katki AG, Collins JM. Metabolism of taxol by humans and ratliver in vitro: a screen for drug interactions and interspecies differences. Cancer Chemother Pharmacol (1995) 36, 107–14.

Taxol (Paclitaxel). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary of product characteristics,August 2005.

Clouse T,Geisler JP, Manahan KJ, Gudenkauf TJ, Linnemeier G, Wiemann MC. Should we be using cimetidine to premedicate patients receiving docetaxel or paclitaxel? Gynecol Oncol (2004) 95, 270–1.

Rischin D,Webster LK, Millward MJ, Linahan BM, Toner GC, Woollett AM, Morton CG, Bishop JF. Cremophor pharmacokinetics in patients receiving 3-, 6-, and 24-hour infusions ofpaclitaxel. J Natl Cancer Inst (1996) 88, 1297–1301.

Cos J,Bellmunt J, Soler C, Ribas A, Lluis JM, Murio JE, Margarit C. Comparative study ofsequential combinations of paclitaxel and methotrexate on a human bladder cancer cell line.Cancer Invest (2000) 18, 429–35.

Taxanes + Cisplatin or Carboplatin - Drug Interactions

The toxicity of paclitaxel given with cisplatin appears to be dependent on order of administration, with more severe myelosuppression occurring if cisplatin is given first. There does notappear to be any sequence dependent interaction for combination of docetaxel with carboplatin or docetaxel with cisplatin.Paclitaxel may reduce thrombocytopenia associated with carboplatin. The combination of carboplatin with paclitaxel appearsto be more neurotoxic than carboplatin with docetaxel.

Clinical evidence,mechanism, importance and management

Several clinical studies have found that severity of thrombocytopenia with combination of paclitaxel and carboplatin was less than that expected with carboplatin alone.(See reference number 1-5) This does not appear to be due to any changes in carboplatin pharmacokinetics. In one study, patients were given carboplatin as a 30-minute infusion, either alone or immediately following paclitaxel 175 mg/m(See reference number 2) as a 3-hour infusion, and it was found that pharmacokinetics of carboplatin were not significantly affected by paclitaxel.(See reference number 6) Similarly,a pharmacokinetic interaction was not noted when paclitaxel and carboplatin were given in either order in another study.(See reference number 1) Other studies found AUC of carboplatin to be similar to that predicted, despite presence of paclitaxel.(See reference number 2,5) Although one study found AUC of carboplatin to be about 12 % lower in presence of paclitaxel,(See reference number 4) same researchers also found that AUC associated with a 50 % decrease in platelet count increased by 68 % (i.e. more carboplatin is needed to cause same degree of thrombocytopenia), which suggests a pharmacodynamic basis for attenuated toxicity of combination.(See reference number 7) Other researchers also reported that AUC of carboplatin causing a 50 % reduction in platelets was about 6.3 mg/mL per minute when given with paclitaxel compared with historical data of 4 mg/mL per minute when given alone.(See reference number 8) Although thrombocytopenia may be lower than expected, myelosuppression (in form of neutropenia) is a dose-limiting toxicity of combination of carboplatin and paclitaxel.(See reference number 1-4) In one study, patients given paclitaxel with carboplatin experienced significantly greater neurotoxicity than those given docetaxel with carboplatin, but regimens were similar in efficacy.(See reference number 9)Further,there appear to be no pharmacokinetic

Early studies of combination of cisplatin and paclitaxel showed that degree of myelosuppression was sequence dependent. When cisplatin was given first,a greater degree of myelosuppression was seen (See reference number 12). Pharmacokinetic studies suggest that sequence-dependent differences in myelosuppression may be due to a 25 % reduction in paclitaxel clearance when cisplatin is given first (See reference number 12). For this reason, manufacturers recommend that paclitaxel is given before cisplatin (See reference number 13,14). There is also some evidence that myelosuppression is greater for combination when paclitaxel is given over 24 hrs as opposed to 3 hrs (See reference number 13). When paclitaxel is given with cisplatin, neurotoxicity (peripheral neuropathy) is common,(See reference number 13) and there is some evidence that this is more severe if paclitaxel is given over 3 hrs as opposed to over 24 hrs (See reference number 15). In one study,(See reference number 16) neurotoxicity was unexpectedly severe when paclitaxel alone was used in patients who had relapsed after treatment with cisplatin; however, this was not case in another similar study (See reference number 17).

In contrast to paclitaxel, early studies did not reveal any obvious sequence dependent toxicity for combination of docetaxel and cisplatin (See reference number 18). In addition,cisplatin did not cause any significant changes in docetaxel pharmacokinetics (See reference number 18,19).

Huizing MT,Giaccone G, van Warmerdam LJC, Rosing H, Bakker PJM, Vermorken JB,Postmus PE, van Zandwijk, Koolen MGJ, ten Bokkel Huinink, van der Vijgh WJF, BierhorstFJ, Lai A, Dalesio O, Pinedo HM, Veenhof CHN, Beijnen JH. Pharmacokinetics of paclitaxeland carboplatin in a dose-escalating and dose-sequencing study in patients with non-smallcell lung cancer. J Clin Oncol (1997) 15, 317–29.

Bookman MA,McGuire WP, Kilpatrick D, Keenan E, Hogan WM, Johnson SW, O’DwyerP, Rowinsky E, Gallion HH, Ozols RF. Carboplatin and paclitaxel in ovarian carcinoma: aphase I study of the Gynecologic Oncology Group. J Clin Oncol (1996) 14, 1895–1902.

Huizing MT,van Warmerdam LJC, Rosing H, Schaefers MCW, Lai A, Helmerhorst TJM,Veenhof CHN, Birkhofer MJ, Rodenhuis S, Beijnen JH, ten Bokkel Huinink WW. Phase Iand pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer. J Clin Oncol (1997) 15, 1953–64.

Belani CP,Kearns CM, Zuhowski EG, Erkmen K, Hiponia D, Zacharski D, Engstrom C, Ramanathan RK, Capozzoli MJ, Aisner J, Egorin MJ. Phase I trial, including pharmacokineticsand pharmacodynamic correlations, of combination paclitaxel and carboplatin in patientswith metastatic non-small-cell lung cancer. J Clin Oncol (1999) 17, 676–84.

Siddiqui N,Boddy AV, Thomas HD, Bailey NP, Robson L, Lind MJ, Calvert AH. A clinicaland pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelialovarian cancer. Br J Cancer (1997) 75, 287–94.

Obasaju CK,Johnson SW, Rogatko A, Kilpatrick D, Brennan JM, Hamilton TC, Ozols RF,O’Dwyer PJ, Gallo JM. Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel. Clin Cancer Res (1996) 2, 549–52.

Kearns CM,Belani CP, Erkmen K, Zuhowski M, Hiponia D, Ergstrom C, Ramanthan R,Trenn M, Aisner J, Ergorin MJ. Reduced platelet toxicity with combination carboplatin & paclitaxel: pharmacodynamic modulation of carboplatin associated thrombocytopenia. Proc Am Soc Clin Oncol (1995) 14, 170.

van Warmerdam LJC,Huizing MT, Giaccone G, Postmus PE, ten Bokkel Huinink WW, vanZandwijk N, Koolen MGJ, Helmerhorst TJM, van der Vijgh WJF, Veenhof CHN, BeijnenJH. Clinical pharmacology of carboplatin administered in combination with paclitaxel. Semin Oncol (1997) 24 (Suppl 2), S2-97–S2-104.

Kaye SB,Vasey PA. Docetaxel in ovarian cancer: phase III perspectives and future development. Semin Oncol (2002) 29 (3 Suppl 12) 22–7.

Oka M,Fukuda M, Nagashima S, Fukuda M, Kinoshita A, Soda H, Doi S, Narasaki F, Suenaga M, Takatani H, Nakamura Y, Kawabata S, Tsurutani J, Kanda T, Kohno S. Phase I studyof second-line chemotherapy with docetaxel and carboplatin in non-small-cell lung cancer.Cancer Chemother Pharmacol (2001) 48, 446–50.

Ando M,Saka H, Ando Y, Minami H, Kuzuya T, Yamamoto M, Watanabe A, Sakai S,Shimokata K, Hasegawa Y. Sequence effect of docetaxel and carboplatin on toxicity, tumorresponse and pharmacokinetics in non-small-cell lung cancer patients: a phase I study of two sequences. Cancer Chemother Pharmacol (2005) 55, 552–8.

Rowkinsky EK,Gilbert M, McGuire WP, Noe DA, Grochow LB, Forastiere AA, EttingerDS, Lubejko BG, Clarke B, Sartorius SE, Cornblath DR, Hendricks CB, Donehower RC. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol (1991) 9, 1692–1703.

Taxol (Paclitaxel). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary of productcharacteristics,August 2005.

Taxol (Paclitaxel). Bristol-Myers Squibb Company. US Prescribing information,March2003.

Connelly E,Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Paclitaxeldelivered as a 3-hr infusion with cisplatin in patients with gynecologic cancers: unexpectedincidence of neurotoxicity. Gynecol Oncol (1996) 62, 166–8.

Cavaletti G,Bogliun G, Marzorati L, Zincone A, Marzola M, Colombo N, Tredici G. Peripheral neurotoxicity of taxol in patients previously treated with cisplatin. Cancer (1995) 75, 1141–50.

McGuire WP,Rowinsky EK, Rosenhein NB, Grumbine FC, Ettinger DS, Armstrong DK,Donehower RC. Taxol: a unique antineoplastic agent with significant activity in advancedovarian epithelial neoplasms. Ann Intern Med (1989) 111, 273–9.

Pronk LC,Schellens JHM, Planting AST, van den Bent MJ, Hilkens PHE, van der BurgMEL, de Boer-Dennert M, Ma J, Blanc C, Harteveld M, Bruno R, Stoter G, Verweij J. PhaseI and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors.J Clin Oncol (1997) 15, 1071–9.

Millward MJ,Zalcberg J, Bishop JF, Webster LK, Zimet A, Rischin D, Toner GC, Laird J,Cosolo W, Urch M, Bruno R, Loret C, James R, Blanc C. Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer. J Clin On-col (1997) 15, 750–8.

Procarbazine + Miscellaneous - Drug Interactions

The effects of drugs that can cause CNS depression or lower bloodpressure may possibly be increased by presence of procarbazine

Clinical evidence,mechanism, importance and management

In one early clinical study,4 of 48 patients developed postural hypotension when treated with procarbazine. In addition,another patient with hypertension (180/110 mmHg) had a progressive fall in blood pressure (to 110/80 mmHg) while being treated with procarbazine (See reference number 1). Additive hypotensive effects may therefore be expected if procarbazine is given to patients taking antihypertensives.

Procarbazine can cause CNS depression ranging from mild drowsiness to profound stupor. In early clinical studies, incidence was variously reported as 8%, 14%, and 31 % (when combined with prochlorperazine, see also (c) below) (See reference number 1-3). Additive CNS depression may therefore be expected if other drugs possessing CNS-depressant activity are given with procarbazine.

An isolated report describes an acute dystonic reaction (difficulty in speaking or moving, intermittent contractions of muscles on left side of neck) in a patient taking procarbazine with prochlorperazine (See reference number 4). Prochlorperazine was thought to have contributed to sedative effects of procarbazine in one early clinical study (See reference number 3).

Samuels ML,Leary WV, Alexanian R, Howe CD, Frei E. Clinical trials with N-isopropyl-:5.5pt; font-weight:normal; color:#000000″>α(2-methylhydrazino)-p-toluamide hydrochloride in malignant lymphoma and other disseminated neoplasia. Cancer (1967) 20. 1187–94.

Stolinsky DC,Solomon J, Pugh RP, Stevens AR, Jacobs EM, Irwin LE, Wood DA, SteinfeldJL, Bateman JR. Clinical experience with procarbazine in Hodgkin’s disease, reticulum cellsarcoma, and lymphosarcoma. Cancer (1970) 26, 984–90.

Brunner KW,Young CW. A methylhydrazine derivative in Hodgkin’s disease and other malignant neoplasms: therapeutic and toxic effects studied in 51 patients. Ann Intern Med (1965)63, 69–86.

Poster DS. Procarbazine-prochlorperazine interaction: an underreported phenomenon. J Med (1978) 9,519–24.

Streptozocin + Phenytoin - Drug Interactions

A single case report indicates that phenytoin can reduce or abolish effects of streptozocin

Clinical evidence,mechanism, importance and management

A patient with an organic hypoglycaemic syndrome, due to a metastatic apud cell carcinoma of pancreas, who was taking streptozocin 2 g daily with phenytoin 400mg daily for 4 days, failed to show expected response until phenytoin was withdrawn (See reference number 1). It would seem that phenytoin inhibited effects of streptozocin by some mechanism as yet unknown. Although this is an isolated case report its authors recommend that concurrent use should be avoided.

1. Koranyi L,Gero L. Influence of diphenylhydantoin on the effect of streptozotocin. BMJ (1979) 1, 127.

Tamoxifen + Rifampicin (Rifampin) - Drug Interactions

Rifampicin increased metabolism of tamoxifen

Clinical evidence,mechanism, importance and management

In 10 healthy men rifampicin 600mg daily for 5 days reduced AUC of a single 80mg dose of tamoxifen by 86%, reduced peak plasma levels by 55%, and reduced half-life by 44%. Similarly, AUC of N-demethyltamoxifen was reduced by 62 % (See reference number 1).

It is likely that rifampicin induces metabolism of tamoxifen by cytochrome P450 isoenzyme CYP3A4, thereby reducing its levels. These findings suggest that efficacy of tamoxifen may be reduced by rifampicin. However,there is some in vitro evidence that suggests that tamoxifen and rifampicin have additive antineoplastic effects in pancreatic carcinoma cell lines (See reference number 2). Also,tamoxifen induces its own metabolism on long-term use (See reference number 3). Thus, further study is needed to assess clinical impact of long-term combined use of these drugs.

1. Kivistö KT,Villikka K, Nyman L, Anttila M, Neuvonen PJ. Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin. Clin Pharmacol Ther (1998) 64, 648–

54.

West CML,Reeves SJ, Brough W. Additive interaction between tamoxifen and rifampicin inhuman biliary tract carcinoma cells. Cancer Lett (1990) 55, 159–63.

Desai PB,Nallani SC, Sane RS, Moore LB, Goodwin BJ, Buckley DJ, Buckley AR. Inductionof cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnaneX receptor by tamoxifen and 4-hydroxytamoxifen. Drug Metab Dispos (2002) 30, 608–12.