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From Grapefruit to Glaucoma: Interactions and Side Effects You Should Be Aware Of Richard L. Ogletree, Jr, Pharm.D. Scope Drug related morbidity and mortality estimated yearly cost in ambulatory setting of $76.6 billion. Most of this is due to hospitalization 8.76 million admissions $47.4 billion 28% of hospitalizations due to drug related causes Arch Int Med 1995;155:1949 Hospitalized Patients 1994 - estimated 33.1 million hospital admissions Estimated 2.2 million serious ADR’s (1 in 15 patients) Estimated 106,000 fatal ADR’s (1 in 315 patients) 4th to 6th leading cause of death in U.S. Lazarou, et al. JAMA 1998;279(15):1200 Definitions ADR - FDA Any adverse event associated with the use of a drug in humans, whether or not considered related, including an adverse event occurring with the use in professional practice; from accidental or intentional overdose, from abuse, from withdrawal, or a failure of expected activity ADR - WHO Any response to a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function ADE - Adverse Drug Event Includes medical errors Categories of ADR’s Predictable or Type A (augmented) side effects toxic effects Non-predictable hypersensitivity or Type B (bizarre) responses idiosyncratic effects Side Effects A result other than the one desired from the agent diphenhydramine - drowsiness nitroglycerin - headache prazosin - nasal stuffiness Toxic Effects Direct cellular function alteration or damage colchicine - GI upset, myopathy digoxin - heart block aminoglycosides - nephrotoxicity Hypersensitivity Reacting to substances in amounts not causing the reaction in most individuals prior exposure is necessary often independent of dose often associated with cell bound IgE antibodies often associated with elevated eosinophil counts (>300) Hypersensitivity Could range from rash to anaphylaxis sulfonamide allergies penicillin allergies many hepatotoxicities Idiosyncratic Effects “Abnormal susceptibility to some drug, protein, or other agent that is peculiar to the individual” Prior exposure not necessary Often genetic acetylator status (INH, procainamide) Glucose 6PD deficiency agranulocytosis with chloramphenicol Assessment of ADR’s Temporal relationship Dechallenge Rechallenge Confounders Can Influence ADR’s Age Weight Race Sex Pregnancy Concomitant diseases Other drugs or food Drug interactions Pharmacological or clinical response to the administration of a combination of drugs is different from that anticipated when drugs are given alone More simply put... When the effects of one drug are changed by presence of another drug, food, drink, or environmental chemical agent Net effect could be ... Enhanced response to one or more of the components Antagonism of effect of one or more of the components Idiosyncratic effect Important: Drug interactions could be desirable multiple mechanisms of action decreasing necessary dose decreasing side effects antidotes Types of Drug Interactions Pharmaceutical incompatibility - including in vivo binding IV admixture incompatibility Tetracyclines and Ca++ or iron Fluoroquinolones and aluminum or iron Phenytoin suspension and NG tube feedings Olestra or orlistat and fat soluble Receptor site interaction Alpha blockers and nasal decongestants Naloxone and opioids Clonidine in opiate withdrawal Vitamin k and coumadin Epinephrine and beta blockers Flumazenil and benzodiazepines Influence of same physiological system Warfarin and NSAIDS Aminoglycosides and neuromuscular blockers Beta blockers, digoxin, verapamil, diltiazem Multiple anti-hypertensives Changes in electrolytes or fluid balance ACE inhibitors and K+ Lithium and high sodium intake Lithium and low sodium diet Ampho B and diuretics Absorption interactions Antacids and drugs Grapefruit juice Doxycycline and digoxin Erythromycin and sulfasalazine Omeprazole and ketoconazole Binding in GI tract Distribution Protein binding mostly theoretical generally transient warfarin and phenytoin Tissue binding quinidine and digoxin Drug metabolism - induction Inducers phenytoin phenobarbital carbamazepine rifampin cigarette smoke St. John’s wort Drug metabolism - induction Be careful with oral contraceptives HRT cyclosporine Drug metabolism - inhibition Inhibitors azole antifungals ketoconazole itraconazole macrolide antibiotic erythromycin clarithromycin cimetidine Drug metabolism - inhibition More inhibitors SSRI’s fluvoxamine paroxetine fluoxetine nefazodone fluoroquinolones amiodarone Grapefruit Juice Caused by furanocoumarin fractions Takes place in GI tract Inhibition of CYP450 1A2 & 3A4 Prevents GI metabolism Increases absorption Increased peak Grapefruit Juice Interactions Calcium channel blockers (felodipine, nisoldipine, nifedipine, verapamil) Cyclosporine Midazolam (oral) Cisapride Simvastatin, lovastatin Predicting Grapefruit Juice Interactions Absorption Bioavailability CYP 450 esp. 3A4 metabolism Look on insert HMG - CoA Reductase Inhibitors (“statins”) Lovastatin (Mevacor®) Pravastatin (Pravachol®) Simvastatin (Zocor®) Fluvastatin (Lescol®) Atorvastatin (Lipitor®) Rosuvastatin (Crestor®) HMG - CoA Reductase Inhibitors (“statins”) Lower cholesterol Inhibit rate limiting reaction in mevalonate pathway Other mevalonic acid products dilochol (liver, retina) ubiquinone (muscles) Concerns with “Statins” Liver problems Concern Muscle with ALT or AST > 3X ULN problems Concern Consider with CK > 10X ULN ubiquinone supplementation in selected patients Liver Monitoring with “Statins” Fluvastatin (Lescol®) bl, 12 wks Simvastatin (Zocor®) bl, 3 mo. (80 mg), 6 mo. 12 mo. Atorvastatin (Lipitor®) bl, 12 wks, 2X/year Lovastatin (Mevacor®) bl, 6 wks, 12 wks, 2X/year Rosuvastatin (Crestor®) bl, 12 wks, 2X/year Note: This is with initiation and with each dose increase. Pravastatin (Pravachol®) bl, prior to dose increase and when “clinically indicated” HMG - CoA Reductase Inhibitors (“statins”) Drugs which increase levels can increase the chance of myopathy or rhabdomyolysis Cyclosporin Gemfibrozil Niacin Erythromycin, Clarithromycin Itraconazole Nefazodone (Serzone®) HMG - CoA Reductase Inhibitors (“statins”) Situations which predispose to myopathy could increase the chance of myopathy or rhabdomyolysis major surgery severe acute infection trauma seizures electrolyte disturbances hypotension HMG - CoA Reductase Inhibitors (“statins”) Concerns unexplained muscle pain accident hospitalization? Theoretical concerns Metformin Stavudine and other NRTI’s weight-lifting? Zocor (simvastatin): Label Change - New Restrictions, Contraindications, and Dose Limitations Posted:06/08/2011 FDA notified healthcare professionals that it is recommending limiting the use of the highest approved dose of the cholesterollowering medication simvastatin (80 mg) because of increased risk of muscle damage. Patients taking simvastatin 80 mg daily have an increased risk of myopathy compared to patients taking lower doses of this drug or other drugs in the same class. This risk appears to be higher during the first year of treatment, is often the result of interactions with certain medicines, and is frequently associated with a genetic predisposition toward simvastatinrelated myopathy. The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure which can be fatal. FDA is requiring changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines. Simvastatin • Contraindicated Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Gemfibrozil Cyclosporine Danazol Simvastatin • Contraindicated Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Gemfibrozil Cyclosporine Danazol Simvastatin 10 mg/day Diltiazem Verapamil 20 mg/day Amiodarone Amlodipine Ranolazine Grapefruit juice Avoid > 1 quart/day Lovastatin - Feb. 28, 2012 • Strong CYP3A4 inhibitors are contraindicated Avoid • 20 mg/ day • Danazol Diltiazem Verapamil 40 mg Cyclosporine Gemfibrozil amiodarone Grapefruit juice Avoid > 1 quart/day Also from Feb. 28, 2012 Added to warnings memory problems new onset diabetes Removed - recommendation for routine liver enzymes Liver injury from statins is rare, and monitoring does not seem to be effective in predicting or preventing such damage. Atorva Fluva Pitava Lova Prava Rosuva Vytorin * Simva %↓ LDL-C ----- 40 mg 1 mg 20 mg 20 mg ----- ----- 10 mg 30% 10 mg 80 mg 2 mg 40 or 80 mg 40 mg ----- ----- 20 mg 38% 20 mg ----- 4 mg 80 mg 80 mg 5 mg 10/10 mg 40 mg 41% 40 mg ----- ----- ----- 10 mg 10/20 mg 80 mg 47% 80 mg ----- ----- ----- 20 mg 10/40 mg ----- 55% ----- ----- ----- 40 mg 10/80 mg ----- 63% *No incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin Quinolones Photosensitivity Drug interactions Rash Dizziness Seizure Insomnia Loss of glycemic control Tendon rupture Quinolones - Tendon Rupture More common in 60 y/o and older Median of 6 days until onset Achilles most common Often bilateral Most recover by 2 months Stop at first sign of tendon pain inflammation, or weakness Use care in weightlifters? Quinolones - Tendon Disorder Case-control study - n = 46,766 Adjusted relative risk > 60 years old current use concurrent steroids 12.8) recent or past use < 60 years old OR 3.5 OR (2.3 - 5.3) 6.2 (3.0 - ns ns van der Linden, et al. BMJ 2002;324:1306-1307 Tetracyclines Photosensitivity Interaction with polyvalent cations Tooth staining Increased intracranial pressure (ICP) Also called BIH (Benign Intracranial Hypertension) or Psuedotumor Cerebri Tetracyclines - Tooth Staining Tetracycline - during tooth formation Binds to calcium Cervical third of tooth (gingival margin) Avoid during pregnancy Avoid in children Tetracyclines - Tooth Staining Minocycline - after tooth eruption Incisional edge, middle third Binds to iron? Binds to glycoproteins oxidizing to form quinone? > 100 mg/day > 1 month duration 3 – 6 % incidence Minocycline - Tooth Staining Prevention Give an antioxidant Give lower doses 100 mg/day for 2 weeks, then 50 mg/day Tetracyclines - BIH Most common with minocycline Also seen with tetracycline and doxycycline More common in normal weight (idiopathic more common in obese) More common in adolescent and young adult women BIH The diagnostic criteria are: Increased intracranial pressure (> 200 mm water) Normal neurological examination except for papilledema and/or sixth nerve palsy No mass or ventricular enlargement on imaging Normal CSF protein and white cell count No clinical or imaging evidence of venous sinus thrombosis There may be decreased visual acuity and visual field defects. Tetracyclines - BIH Not associated with dose Often occurs in first 2 to 4 weeks of therapy Other drugs causing BIH Vitamin A analogs (isotretinoin) Steroids (esp in withdrawal) Tetracyclines - BIH Ask about headaches tinnitis blurred vision double vision Check for papilledema Levothyroxine Very commonly used Hypothyroidism primary secondary Weight loss - not a good idea Anemia predisposes to intolerance watch for tachycardia, palpitations, nervousness correct low Hct (esp if below 28) before starting start low 25 mcg or less Levothyroxine interactions Calcium Iron (including prenatal vitamins or other vitamin/mineral preps) Soy protein all decrease absorption separate by at least 2 hours SSRI’s Anxiety Insomnia Sexual dysfunction Withdrawal Interaction with DM cough preps Tooth grinding GI bleeds SSRI withdrawal Disequilibrium dizziness vertigo ataxia swimming or spaced out feeling impaired coordination SSRI withdrawal GI disturbances nausea vomiting diarrhea anorexia Flu-like symptoms SSRI withdrawal Sensory disturbances auditory hallucinations paresthesias electrical shock sensations CNS symptoms agitation confusion headache lethargy SSRI withdrawal Sleep disturbances insomnia nightmares vivid relapse dreams of depression SSRI withdrawal most common Dizziness Nausea Lethargy Headache SSRI withdrawal Onset - 1 to 5 days after disruption (longer for fluoxetine) Duration - 1 to 3 weeks Prevention - slow taper of meds Ginger has been helpful with nausea and vertigo SSRI - DM interaction Dextromethorphan D-isomer of levorphanol Cough suppressant NMDA antagonist Decreases glutamate excitability Dextromethorphan Cough/cold preps Adjuvant for pain management (including neuropathic pain) Decrease opioid tolerance Interacts with MOAI’s Interacts with SSRI’s Serotonin syndrome Mental status changes Tremor Restlessness Incoordination Shivering Increased temperature Serotonin syndrome Diaphoresis Hyperreflexia Myoclonus Diarrhea Convulsions Could be fatal SSRI - DM interaction If needing a cough suppressant use: Benzonatate Carbetapentane combinations SSRI Induced Bruxism Often nocturnal More common in women Probably dopaminergic (similar to neuroleptics) 2 to 4 weeks from starting therapy (reported range - 1 week to 11 months) Sometimes, first noticed by dentist SSRI Induced Bruxism Ask about/look for muscle tension headache joint pain (tmj) muscle pain (chewing muscles) masseter hypetrophy SSRI Induced Bruxism Management Changing agents - probably not helpful Decrease dose of SSRI Buspirone 5 - 30 mg usually hs dosing should have an effect in 1 to 4 weeks SSRI’s and GI Bleeds SSRI antidepressants most Non 1.9) OR 3.0 (2.1 - 4.4) likely - trazodone SSRI antideps OR 1.4 (1.1 - Abajo, et al. BMJ 1999;319:1106-1109 SSRI’s and GI Bleeds Not adjusted for NSAID use SSRI antidepressants OR 2.6 (1.7 - 3.8) NSAID’s OR 3.7 (3.2 - 4.4) SSRI + NSAID OR 15.6 (6.6 - 36.6) Abajo, et al. BMJ 1999;319:1106-1109 8/24/2012 Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide) The U.S. Food and Drug Administration (FDA) is informing healthcare professionals and patients that the antidepressant Celexa (citalopram hydrobromide; also marketed as generics) should no longer be used at doses greater than 40 mg per day because it can cause abnormal changes in the electrical activity of the heart. Studies did not show a benefit in the treatment of depression at doses higher than 40 mg per day. Maximum dose - 40 mg/day due to prolongation of QT interval Max of 20 mg/day 60 YO and older liver impairment poor CYP2C19 metabolizers taking cimetidine (Tagamet) Not recommended for CHF patients bradyarrhythmias, concomitant use of medications that prolong the QT interval Monitor ECGs and electrolytes Discontinue if patient has persistent QTc measurements of > 500 ms. Zyvox The U.S. Food and Drug Administration (FDA) has received reports of serious central nervous system (CNS) reactions when the antibacterial drug linezolid (marketed as Zyvox) is given to patients taking psychiatric medications that work through the serotonin system of the brain (serotonergic psychiatric medications). Linezolid Inhibits monoamine oxidase A Results in decreased serotonin metabolism Serotonin toxicity = Serotonin syndrome Should avoid linezolid in patients taking serotonergic drugs unless treating: VRE Noscomial pneumonia Complicated skin and skin structure infections (including MRSA) Emergent cases Use alternate therapy for linezolid Stop serotonergic drug and monitor patient for CNS toxicity for: Two weeks (five with fluoxetine) 24 hours after last dose of linezolid whichever comes first Non-emergent D/C cases serotonergic drug 2 weeks before starting linezolid (5 weeks for fluoxetine) Resume serotonergic drug 24 hours after last dose of linezolid Educate patient of signs and symptoms of Serotonin Syndrome Report adverse events to FDA MedWatch Serotonergic Psychiatric Medications SSRIs SNRIs Tricyclics MAOIs Other: Amoxapine Maprotiline Nefazodone Trazodone Buproprion Buspirone Vilazodone Serotonin Syndrome Symptoms Tremor Altered mental status Clonus Muscular hypertonicity hyperthermia 7/26/2011 Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications The U.S. Food and Drug Administration (FDA) has received reports of serious central nervous system (CNS) reactions when the drug methylene blue is given to patients taking psychiatric medications that work through the serotonin system of the brain (serotonergic psychiatric medications). Methylene blue is commonly used in diagnostic procedures and is also used to treat a number of medical conditions. Methylene blue Monoamine oxidase inhibitor properties Urgent treatment of: Methemoglobinemia Ifosfamide-induced Cyanide poisoning encephalopathy Also Urinary medications UTA Urogesic blue Antihistamine/Decongestant Combinations Newer antihistamines Less sedation Long duration of activity Good safety profiles Antihistamine/Decongestant Combinations Same decongestants (usually pseudoephedrine) Increased heart rate Increased blood pressure Prostate disturbance Decreased appetite Anxiety Insomnia Decongestant Profiles 500 450 400 350 300 250 200 150 100 50 0 Claritin D 12 Zyrtec D Allegra D Claritin D 24 3.9 4.4 5 7 3/12/2013 Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms The U.S. Food and Drug Administration (FDA) is warning the public that azithromycin (Zithromax or Zmax) can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm. Patients at particular risk for developing this condition include those with known risk factors such as: existing QT interval prolongation low blood levels of potassium or magnesium a slower than normal heart rate use of certain drugs used to treat abnormal heart rhythms arrhythmias 6/25/2014 FDA warns of rare but serious hypersensitivity reactions with certain over-the-counter topical acne products The U.S. Food and Drug Administration (FDA) is warning that certain over-thecounter (OTC) topical acne products can cause rare but serious and potentially lifethreatening allergic reactions or severe irritation. The hypersensitivity reactions may occur within minutes to a day or longer after product use. The OTC topical acne products of concern are marketed under various brand names such as: Proactiv Neutrogena MaxClarity Oxy Ambi Aveeno Clean & Clear They are available as gels, lotions, face washes, solutions, cleansing pads, toners, face scrubs, and other products. Anticholinergic Drugs Toxidrome mneumonic Blind as a bat Dry as a bone Mad as a hatter Hot as a hare Red as a beet Counseling points Blind as a bat – blurry vision dilated pupils caution with driving recommend sunglasses Dry as a bone decreased saliva increased risk of cavities recommend dental exams Mad as a hatter confusion memory loss Counseling points Hot as a hare Red as a beet Both are associated with heat intolerance Counsel about heat precautions Anticholinergics - uses GI dicyclomine hyoscyamine Overactive Bladder oxybutynin tolterodine darefenacin solefenacin Anticholinergics - uses Excessive salivation glycopyrrolate atropine scopolamine Antipsychotic induced EPS benztropine trihexyphenidyl Anticholinergic Drugs A drug interaction of note All solid oral dosage forms of potassium chloride are contraindicated in any patient in whom there is structural, pathological (e.g., diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract. Prepare an aqueous (water) suspension as follows: Place the whole tablet(s) in approximately one-half glass of water (4 fluid ounces). Allow approximately 2 minutes for the tablet(s) to disintegrate. Stir for about half a minute after the tablet(s) has disintegrated. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw. Add another one fluid ounce of water, swirl, and consume immediately. Then, add an additional one fluid ounce of water, swirl, and consume immediately. Other agents with potential for heat intolerance Amphetamines Pseudoephedrine Phenylepherine Zonisamide Topiramate Other Side Effects with Topiramate Taste disturbance Confusion Word-finding difficulties Loss of appetite Visual disturbance Lotrisone® Antifungal/Corticosteroid Often for “jock itch” or diaper rash Skin thinning Functional “occlusive dressing” Systemic side effects “Addictive” Glucocorticoids - Systemic Increased blood glucose HPA axis suppression Decreased bone mineral density Skin thinning Withdrawal Glaucoma Glaucoma Or increased intraocular pressure Most common with ophthalmic dosing use special care after LASIK Also seen with systemic therapy What about inhaled steroids? Inhaled Glucocorticoids Glaucoma Family or IOP risk history OR High doses and fam hx OR 2.6 6.3 (1.2 - 5.8) (1.0 - 38.6) No association when no fam. Hx Ask about family history of glaucoma or IOP when prescribing inhaled steroids Mitchell, et al Ophthalmology 1999;106:2301-2306 Report ADR’s Larger patient populations Open-ended time frame Not limited to “healthy adults” JCAHO requires an institutional policy Check Updates Clin-Alert Australian Adverse Drug Reaction Bulletin http://www.health.gov.au/tga/adr/aad rb.htm Med-Safe (New Zealand) http://www.medsafe.govt.nz/profs.htm Dear Doctor letters Institutional newsletter Lactulose A theoretical hazard may exist for patients being treated with lactulose solution who may be required to undergo electrocautery procedures during proctoscopy or colonoscopy. Accumulation of H2 gas in significant concentration in the presence of an electrical spark may result in an explosive reaction. Although this complication has not been reported with lactulose, patients on lactulose therapy undergoing such procedures should have a thorough bowel cleansing with a non-fermentable solution. Insufflation of CO2 as an additional safeguard may be pursued but is considered to be a redundant measure. Brooke Tullos Mary Wooten Infectious Disease Infectious Disease Travis King Travis King KABOOM ! How do you say you’re sorry? FDA Alerts 7/09/2015 FDA strengthens warning that non-aspirin nonsteroidal antiinflammatory drugs (NSAIDs) can cause heart attacks or strokes The U.S. Food and Drug Administration (FDA) is strengthening an existing label warning that nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the chance of a heart attack or stroke. Based on our comprehensive review of new safety information, the FDA is requiring updates to the drug labels of all prescription NSAIDs. The FDA will also request updates to the OTC nonaspirin NSAID Drug Facts labels. 7/01/2015 FDA evaluating the potential risks of using codeine cough-andcold medicines in children
