Atorvastatin drug interactions: Difference between revisions

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__NOTOC__
#REDIRECT [[Atorvastatin#Drug Interactions]]
{{Atorvastatin}}
{{CMG}}; {{AE}} {{PB}}
 
 
The risk of [[myopathy]] during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of [[niacin]], [[cyclosporine]], or strong CYP 3A4 inhibitors (e.g., [[clarithromycin]], [[HIV protease inhibitor]]s, and [[itraconazole]]) [see Warnings and Precautions, Skeletal Muscle (5.1) and Clinical Pharmacology (12.3)].
 
====Strong Inhibitors of CYP 3A4====
 
Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of Atorvastatin with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.
 
====[[Clarithromycin]]====
 
Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin 80 mg with [[clarithromycin]] (500 mg twice daily) compared to that of Atorvastatin alone [see Clinical Pharmacology (12.3)]. Therefore, in patients taking [[clarithromycin]], caution should be used when the Atorvastatin dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)].
 
====Combination of Protease Inhibitors====
 
Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of Atorvastatin alone [see Clinical Pharmacology (12.3)]. Therefore, in patients taking the [[HIV protease inhibitor]] [[tipranavir]] plus [[ritonavir]], or the [[hepatitis C]] protease inhibitor [[telaprevir]], concomitant use of Atorvastatin should be avoided. In patients taking the [[HIV protease inhibitor]] [[lopinavi]]r plus [[ritonavir]], caution should be used when prescribing Atorvastatin and the lowest dose necessary should be used. In patients taking the [[HIV protease inhibitors]] [[saquinavir]] plus [[ritonavir]], [[darunavi]]r plus [[ritonavir]], [[fosamprenavir]], or [[fosamprenavir]] plus ritonavir, the dose of Atorvastatin should not exceed 20 mg and should be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)]. In patients taking the HIV protease inhibitor [[nelfinavir]] or the [[hepatitis C]] protease inhibitor [[boceprevir]], the dose of Atorvastatin should not exceed 40 mg and close clinical monitoring is recommended.
 
====[[Itraconazole]]====
 
Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin 40 mg and [[itraconazole]] 200 mg [see Clinical Pharmacology (12.3)]. Therefore, in patients taking [[itraconazole]], caution should be used when the Atorvastatin dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)].
 
====Grapefruit Juice====
 
Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).
 
====[[Cyclosporine]]====
 
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., [[cyclosporine]]) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin 10 mg and [[cyclosporine]] 5.2 mg/kg/day compared to that of Atorvastatin alone [see Clinical Pharmacology (12.3)]. The co-administration of Atorvastatin with cyclosporine should be avoided [see Warnings and Precautions, Skeletal Muscle (5.1)].
 
====[[Gemfibrozil]]====
 
Due to an increased risk of myopathy/rhabdomyolysis when [[HMG-CoA reductase]] inhibitors are co-administered with gemfibrozil, concomitant administration of Atorvastatin with [[gemfibrozil]] should be avoided [see Warnings and Precautions (5.1)].
 
====Other [[Fibrates]]====
 
Because it is known that the risk of [[myopathy]] during treatment with [[HMG-CoA reductase]] inhibitors is increased with concurrent administration of other fibrates, Atorvastatin should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1)].
 
====[[Niacin]]====
 
The risk of skeletal muscle effects may be enhanced when Atorvastatin is used in combination with niacin; a reduction in Atorvastatin dosage should be considered in this setting [see Warnings and Precautions (5.1)].
 
====[[Rifampin]] or other Inducers of Cytochrome P450 3A4====
 
Concomitant administration of Atorvastatin with inducers of cytochrome P450 3A4 (e.g., [[efavirenz]], [[rifampin]]) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of Atorvastatin with rifampin is recommended, as delayed administration of Atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
 
====[[Digoxin]]====
 
When multiple doses of Atorvastatin and [[digoxin]] were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
 
==== [[Oral Contraceptive]]s====
 
Co-administration of Atorvastatin and an oral contraceptive increased AUC values for norethindrone and [[ethinyl estradiol]] [see Clinical Pharmacology (12.3)]. These increases should be considered when selecting an oral contraceptive for a woman taking Atorvastatin.
 
====[[Warfarin]]====
 
Atorvastatin had no clinically significant effect on [[prothrombin time]] when administered to patients receiving chronic warfarin treatment.
====[[Colchicine]]====
 
Cases of [[myopathy]], including [[rhabdomyolysis]], have been reported with atorvastatin co-administered with [[colchicine]], and caution should be exercised when prescribing atorvastatin with [[colchicine]].<ref name="dailymed.nlm.nih.gov">{{Cite web  | last =  |first =  | title = LIPITOR (ATORVASTATIN CALCIUM) TABLET, FILM COATED [PARKE-DAVIS DIV OF PFIZER INC] | url =http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c6e131fe-e7df-4876-83f7-9156fc4e8228#nlm34089-3 | publisher =  | date =  | accessdate = }}</ref>
 
 
==Major Interactions==
{{refbegin|3}}
* [[Agenerase]]
* [[amprenavir]]
* [[Antara]]
* [[Aptivus]]
* [[atazanavir]]
* [[Atromid-S]]
* [[B-3-50]]
* [[B3-500-Gr]]
* [[Biaxin]]
* [[Biaxin XL]]
* [[Biaxin XL-Pak]]
* [[clarithromycin]]
* [[clarithromycin extended release]]
* [[clofibrate]]
* [[clotrimazole]]
* [[conivaptan]]
* [[Crixivan]]
* [[cyclosporine]]
* [[danazol]]
* [[Danocrine]]
* [[Diflucan]]
* [[Dom-Fenofibrate]]
* [[E-Mycin]]
* [[E.E.S. Granules]]
* [[E.E.S.-200]]
* [[E.E.S.-400]]
* [[E.E.S.-400 Filmtab]]
* [[Ery-Tab]]
* [[Eryc]]
* [[EryPed]]
* [[EryPed 200]]
* [[EryPed 400]]
* [[Erythrocin Lactobionate]]
* [[Erythrocin Stearate Filmtab]]
* [[Erythrocot]]
* [[erythromycin]]
* [[erythromycin base]]
* [[erythromycin estolate]]
* [[erythromycin ethylsuccinate]]
* [[erythromycin lactobionate]]
* [[erythromycin stearate]]
* [[fenofibrate]]
* [[Fenoglide]]
* [[fluconazole]]
* [[Fortovase]]
* [[fosamprenavir]]
* [[gemfibrozil]]
* [[Gengraf]]
* [[Ilosone]]
* [[Ilotycin Gluceptate]]
* [[indinavir]]
* [[Invirase]]
* [[itraconazole]]
* [[Ketek]]
* [[Ketek Pak]]
* [[ketoconazole]]
* [[Lexiva]]
* [[Lipidil EZ]]
* [[Lipidil Micro]]
* [[Lipidil Supra]]
* [[Lipofen]]
* [[Lofibra]]
* [[Lopid]]
* [[mibefradil]]
* [[miconazole]]
* [[Monistat I.V.]]
* [[MY-E]]
* [[Mycelex Troche]]
* [[nefazodone]]
* [[nelfinavir]]
* [[Neoral]]
* [[niacin]]
* [[niacin extended release]]
* [[Niacin SR]]
* [[Niacor]]
* [[Niacor B3]]
* [[Niaspan ER]]
* [[Niaspan ER Starter Pack]]
* [[Nico-400]]
* [[Nicobid Tempules]]
* [[Nicolar]]
* [[Nicotinex]]
* [[Nicotinic Acid]]
* [[Nizoral]]
* [[Norvir]]
* [[Norvir Soft Gelatin]]
* [[Noxafil]]
* [[PCE Dispertab]]
* [[posaconazole]]
* [[Posicor]]
* [[Reyataz]]
* [[ritonavir]]
* [[Robimycin]]
* [[Sandimmune]]
* [[saquinavir]]
* [[saquinavir mesylate]]
* [[Serzone]]
* [[Slo-Niacin]]
* [[Sporanox]]
* [[Tao]]
* [[telithromycin]]
* [[Telzir]]
* [[tipranavir]]
* [[TriCor]]
* [[Triglide]]
* [[troleandomycin]]
* [[Vaprisol]]
* [[Viracept]]
* [[vitamin B3]]
{{refend}}
 
==Moderate Interactions==
{{refbegin|3}}
* [[8-Mop]]
* [[Abraxane]]
* [[Accolate]]
* [[Adalat]]
* [[Adalat CC]]
* [[Afeditab CR]]
* [[aliskiren]]
* [[aminolevulinic acid topical]]
* [[amiodarone]]
* [[Antabuse]]
* [[aprepitant]]
* [[Arava]]
* [[Arranon]]
* [[Avonex]]
* [[Avonex Prefilled Syringe]]
* [[azithromycin]]
* [[Azithromycin 3 Day Dose Pack]]
* [[Azithromycin 5 Day Dose Pack]]
* [[azithromycin extended release]]
* [[AZT]]
* [[Betaseron]]
* [[bortezomib]]
* [[bosentan]]
* [[bromocriptine]]
* [[Calan]]
* [[Calan SR]]
* [[carboplatin]]
* [[Carboplatin Novaplus]]
* [[Cardizem]]
* [[Cardizem CD]]
* [[Cardizem LA]]
* [[Cardizem Monovial]]
* [[Cardizem SR]]
* [[Cardoxin]]
* [[Cartia XT]]
* [[Chloracol]]
* [[chloramphenicol]]
* [[Chloromycetin]]
* [[Chloromycetin Sodium Succinate]]
* [[cholestyramine]]
* [[Cholestyramine Light]]
* [[cisplatin]]
* [[clofarabine]]
* [[Clolar]]
* [[clopidogrel]]
* [[Cordarone]]
* [[Cordarone I.V.]]
* [[Covera-HS]]
* [[Cubicin]]
* [[D.H.E. 45]]
* [[d4T]]
* [[dalfopristin]]
* [[daptomycin]]
* [[darunavir]]
* [[dasatinib]]
* [[ddC]]
* [[ddI]]
* [[delavirdine]]
* [[didanosine]]
* [[didanosine delayed release capsule]]
* [[Digitek]]
* [[digoxin]]
* [[digoxin capsule]]
* [[dihydroergotamine]]
* [[dihydroergotamine nasal]]
* [[Dilacor XR]]
* [[Diltia XT]]
* [[diltiazem]]
* [[diltiazem 24 hour extended release]]
* [[diltiazem extended release]]
* [[Diltiazem Hydrochloride CD]]
* [[Diltiazem Hydrochloride SR]]
* [[Diltiazem Hydrochloride XR]]
* [[Diltiazem Hydrochloride XT]]
* [[Diquinol]]
* [[disulfiram]]
* [[docetaxel]]
* [[echinacea]]
* [[efavirenz]]
* [[Eloxatin]]
* [[Emend]]
* [[Emend 3-Day]]
* [[Emend for Injection]]
* [[Ergomar]]
* [[ergotamine]]
* [[esomeprazole]]
* [[etravirine]]
* [[ezetimibe]]
* [[Fasigyn]]
* [[FK506]]
* [[Flagyl]]
* [[Flagyl 375]]
* [[Flagyl ER]]
* [[Flagyl I.V.]]
* [[Flagyl I.V. RTU]]
* [[fluvoxamine]]
* [[fluvoxamine extended release]]
* [[Folex PFS]]
* [[fosaprepitant]]
* [[Furadantin]]
* [[Gleevec]]
* [[goldenseal]]
* [[grepafloxacin]]
* [[Hivid]]
* [[hypericum perforatum]]
* [[imatinib]]
* [[INH]]
* [[Intelence]]
* [[interferon beta-1a]]
* [[interferon beta-1b]]
* [[iodoquinol]]
* [[isoniazid]]
* [[Isoptin]]
* [[Isoptin I.V.]]
* [[Isoptin SR]]
* [[ixabepilone]]
* [[Ixempra]]
* [[Lanoxicaps]]
* [[Lanoxin]]
* [[lanreotide]]
* [[lansoprazole]]
* [[lapatinib]]
* [[leflunomide]]
* [[Levulan Kerastick]]
* [[Luvox]]
* [[Luvox CR]]
* [[Macrobid]]
* [[Macrodantin]]
* [[methotrexate]]
* [[Methotrexate Sodium Preservative Free]]
* [[methoxsalen]]
* [[Metro I.V.]]
* [[metronidazole]]
* [[metronidazole extended release]]
* [[Metryl]]
* [[midazolam]]
* [[Mifeprex]]
* [[mifepristone]]
* [[Migranal]]
* [[naltrexone]]
* [[Navelbine]]
* [[nelarabine]]
* [[nevirapine]]
* [[Nexium]]
* [[Nexium I.V.]]
* [[Nifediac CC]]
* [[Nifedical XL]]
* [[Nifedipine]]
* [[Nifedipine extended release]]
* [[nilotinib]]
* [[Nitro Macro]]
* [[nitrofurantoin]]
* [[nitrofurantoin dual release]]
* [[nitrofurantoin macrocrystals]]
* [[nitrofurantoin regular release]]
* [[Nydrazid]]
* [[octreotide]]
* [[omeprazole]]
* [[Oncovin]]
* [[Onxol]]
* [[oxaliplatin]]
* [[oxcarbazepine]]
* [[Oxsoralen-Ultra]]
* [[Pacerone]]
* [[paclitaxel]]
* [[paclitaxel protein-bound]]
* [[pantoprazole]]
* [[Paraplatin]]
* [[Parlodel]]
* [[pectin]]
* [[Platinol-AQ]]
* [[Plavix]]
* [[Prevacid]]
* [[Prevacid I.V.]]
* [[Prevacid SoluTab]]
* [[Prevalite]]
* [[Prezista]]
* [[Priftin]]
* [[Prilosec]]
* [[Prilosec OTC]]
* [[Procardia]]
* [[Procardia XL]]
* [[Prograf]]
* [[Protonix]]
* [[Protonix IV]]
* [[Protostat]]
* [[Questran]]
* [[Questran Light]]
* [[Rapamune]]
* [[Raxar]]
* [[Rebif]]
* [[Rescriptor]]
* [[Retrovir]]
* [[ReVia]]
* [[Rheumatrex Dose Pack]]
* [[Rifadin]]
* [[Rifadin IV]]
* [[rifampin]]
* [[rifapentine]]
* [[Rimactane]]
* [[RU-486]]
* [[Sandostatin]]
* [[Sandostatin LAR Depot]]
* [[sirolimus]]
* [[Somatuline Depot]]
* [[Sprycel]]
* [[St. John's wort]]
* [[stavudine]]
* [[stavudine extended release]]
* [[Sustiva]]
* [[tacrolimus]]
* [[Tasigna]]
* [[Taxol]]
* [[Taxotere]]
* [[Taztia XT]]
* [[Tekturna]]
* [[telbivudine]]
* [[temsirolimus]]
* [[thalidomide]]
* [[Thalomid]]
* [[thioguanine]]
* [[Tiazac]]
* [[Tindamax]]
* [[tinidazole]]
* [[Torisel]]
* [[Tracleer]]
* [[Trexall]]
* [[Trileptal]]
* [[Tykerb]]
* [[Tyzeka]]
* [[Uvadex]]
* [[Velban]]
* [[Velcade]]
* [[verapamil]]
* [[verapamil 24 hour extended release]]
* [[verapamil extended release]]
* [[Verelan]]
* [[Verelan PM]]
* [[Versed]]
* [[verteporfin]]
* [[VFEND]]
* [[Videx]]
* [[Videx EC]]
* [[vinblastine]]
* [[Vincasar PFS]]
* [[vincristine]]
* [[vinorelbine]]
* [[Viramune]]
* [[Visudyne]]
* [[Vivitrol]]
* [[voriconazole]]
* [[Yodoxin]]
* [[Z-Pak]]
* [[zafirlukast]]
* [[zalcitabine]]
* [[Zegerid (Original Formulation)]]
* [[Zerit]]
* [[Zerit XR]]
* [[Zetia]]
* [[zidovudine]]
* [[Zithromax]]
* [[Zithromax IV]]
* [[Zithromax TRI-PAK]]
* [[Zithromax Z-Pak]]
* [[Zmax]]
{{refend}}
 
==Minor Interactions==
{{refbegin|3}}
* [[Adgyn Estro]]
* [[Aerodiol]]
* [[Aloh-Gel]]
* [[Alora]]
* [[Alternagel]]
* [[Alu-Cap]]
* [[Alu-Tab]]
* [[aluminum hydroxide]]
* [[Amen]]
* [[Amphojel]]
* [[anisindione]]
* [[Aquest]]
* [[armodafinil]]
* [[Aygestin]]
* [[Bedol]]
* [[bexarotene]]
* [[Camila]]
* [[Cenestin]]
* [[chlorotrianisene]]
* [[Climara]]
* [[Climaval]]
* [[Climodien]]
* [[Clinagen LA 40]]
* [[Colestid]]
* [[Colestid Flavored]]
* [[colestipol]]
* [[Concentrated Phillips Milk of Magnesia]]
* [[conjugated estrogens]]
* [[conjugated estrogens synthetic A]]
* [[conjugated estrogens synthetic B]]
* [[conjugated estrogens topical]]
* [[Coumadin]]
* [[Crinone]]
* [[Curretab]]
* [[Cyclogest]]
* [[Cycrin]]
* [[Delestrogen]]
* [[DELIDOSE]]
* [[Delta-Lutin]]
* [[Dep Gynogen]]
* [[Depo-Estradiol]]
* [[Depo-Provera]]
* [[Depo-Provera Contraceptive]]
* [[depo-subQ provera 104]]
* [[Depogen]]
* [[Dermestril]]
* [[Dermestril - Septem]]
* [[Dermestril Septem]]
* [[desogestrel]]
* [[Dialume]]
* [[dicumarol]]
* [[dienestrol topical]]
* [[Dioval 40]]
* [[Dioval XX]]
* [[Divigel 0.25 mg/packet]]
* [[Divigel 0.5 mg/packet]]
* [[Divigel 1 mg/packet]]
* [[drospirenone]]
* [[Dura-Estrin]]
* [[Duragen]]
* [[Duralutin]]
* [[Dynacirc]]
* [[Dynacirc CR]]
* [[Elestrin]]
* [[Elleste Solo]]
* [[Endometrin]]
* [[Enjuvia]]
* [[Errin]]
* [[Esclim]]
* [[esterified estrogens]]
* [[Estinyl]]
* [[Estra-C]]
* [[Estra-V 40]]
* [[Estrace]]
* [[Estrace Vaginal Cream]]
* [[Estraderm]]
* [[Estraderm MX]]
* [[Estraderm TTS]]
* [[estradiol]]
* [[estradiol acetate]]
* [[estradiol benzoate]]
* [[estradiol cypionate]]
* [[ESTRADIOL G GAM]]
* [[Estradiol Patch]]
* [[estradiol topical]]
* [[estradiol valerate]]
* [[Estradot]]
* [[Estradot 100]]
* [[Estradot 37.5]]
* [[Estradot 50]]
* [[Estradot 75]]
* [[Estragyn 5]]
* [[Estragyn LA 5]]
* [[ESTRAPATCH]]
* [[Estrasorb]]
* [[ESTREVA]]
* [[Estring]]
* [[Estro-A]]
* [[Estro-Cyp]]
* [[Estro-L.A.]]
* [[Estro-Span 40]]
* [[Estrofem]]
* [[Estrogel]]
* [[estrone]]
* [[Estrone AQ]]
* [[estropipate]]
* [[estropipate topical]]
* [[ethinyl estradiol]]
* [[ethynodiol]]
* [[etonogestrel]]
* [[Evamist]]
* [[Evorel]]
* [[Ex-Lax Milk of Magnesia]]
* [[Fematrix]]
* [[Fempatch]]
* [[Femring]]
* [[FEMSEPT]]
* [[FemSeven]]
* [[FemSeven Sequi Phase I]]
* [[FemTab]]
* [[Femtrace]]
* [[Femtran]]
* [[First Progesterone MC10]]
* [[First Progesterone MC5]]
* [[FIRST-Progesterone VGS 100]]
* [[FIRST-Progesterone VGS 200]]
* [[FIRST-Progesterone VGS 25]]
* [[FIRST-Progesterone VGS 400]]
* [[FIRST-Progesterone VGS 50]]
* [[Gestone]]
* [[Gynodiol]]
* [[Gynogen LA 20]]
* [[hydroxyprogesterone]]
* [[Hylutin]]
* [[Hyprogesterone]]
* [[Implanon]]
* [[isradipine]]
* [[isradipine extended release]]
* [[Jantoven]]
* [[Jolivette]]
* [[Kestrone 5]]
* [[levonorgestrel]]
* [[magnesium hydroxide]]
* [[Medidiol 10]]
* [[medroxyprogesterone]]
* [[Menaval-20]]
* [[Menest]]
* [[Menopause Formula Progesterone]]
* [[Menorest]]
* [[Menorest Patch]]
* [[Menostar]]
* [[mestranol]]
* [[Mg hydroxide]]
* [[Milk of Magnesia]]
* [[Miradon]]
* [[Mirena]]
* [[modafinil]]
* [[Nor-QD]]
* [[Nora-Be]]
* [[norelgestromin]]
* [[norethindrone]]
* [[norethindrone acetate]]
* [[norethindrone topical]]
* [[norgestimate]]
* [[norgestrel]]
* [[Norplant System]]
* [[Nuvelle TS Phase I]]
* [[Nuvigil]]
* [[Oesclim]]
* [[Oestradiol]]
* [[Oestradiol Implants]]
* [[Oestrodose]]
* [[Oestrogel]]
* [[Oestrogel Pump-Pack]]
* [[Ogen 0.625]]
* [[Ogen 1.25]]
* [[Ogen 2.5]]
* [[Ogen Vaginal Cream]]
* [[Organon Oestradiol]]
* [[Orion Progesterone]]
* [[Oromone]]
* [[Ortho Dienestrol]]
* [[Ortho Micronor]]
* [[Ortho-Est]]
* [[Ovrette]]
* [[Phillips Milk of Magnesia]]
* [[Plan B]]
* [[Premarin]]
* [[Premarin Intravenous]]
* [[Premarin Vaginal]]
* [[Primogyn Depot]]
* [[Prochieve]]
* [[Prodrox]]
* [[Progest]]
* [[Progestasert System]]
* [[progesterone]]
* [[progesterone topical]]
* [[Progynova]]
* [[Progynova TS]]
* [[Prometrium]]
* [[Provames]]
* [[Provera]]
* [[Provigil]]
* [[quinestrol]]
* [[Sandrena]]
* [[Systen]]
* [[Tace]]
* [[Targretin]]
* [[Thais]]
* [[Thaissept]]
* [[Vagifem]]
* [[Valergen]]
* [[Vivelle]]
* [[Vivelle-Dot]]
* [[Vivelledot]]
* [[Warfarin]]
* [[Zumenon]]
{{refend}}
 
 
==References==
{{Reflist}}
 
 
 
{{FDA}}
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[[Category:Drugs]]

Latest revision as of 14:41, 22 July 2014