Drug Safety and Availability.Medication Guides are paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. FDA requires that Medication Guides be issued with certain prescribed drugs and biological products when the Agency determines that: certain information is necessary to prevent serious adverse effects patient decision-making should be informed by information about a known serious side effect with a product, or patient adherence to directions for the use of a product are essential to its effectiveness. Information Update (3/2017) Medication Guides are updated as they appear in new drug labeling. Please note that we link directly into the drug label to the first page of the medication guide. Medication Guides may or may not be at the end of the label. Before printing check the number of pages of the Medi

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Medication Guides are available for these products:

https://www.fda.gov/Drugs/DrugSafety/ucm085729.htm

*biologic or drug/biologic combination

• Abilify (aripiprazole) [8/2016 version]  
• Abilify Maintena (aripiprazole) [1/2016 version]
• Absorica (isotrentinoin) [2014 version]
• Abstral (fentanyl) [2016 version]
• Aciphex (rabeprazole sodium) [4/2016 version]
• Aciphex DR (rabeprazole sodium) [4/2016 version]
• Accutane (isotretinoin) [2010 version]
• Actemra (tocilizumab) [5/2017 version] 
• Actiq (fentanyl citrate) [2016 version]
• Actonel (risedronate sodium) [2015 version]
• Actonel with Calcium (risedronate sodium and calcium carbonate) [2015 version]
• Actoplus Met (metformin hydrochloride and pioglitazone hydrochloride) [2014 version] 
• Actoplus Met XR (metformin hydrochloride and pioglitazone hydrochloride) [2016 version]
• Actos (pioglitazone hydrchloride) [2016 version]
• Adasuve (loxapine) [2016 version]
• Adderall (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets) [2015 version]
• Adderall XR (dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate) [2015 version]
• Addyi (flibanserin) [2015 version]
• Adempas (riociguat) [2017 version]
• Adlyxin (lixisenatide) {2016 version]
• Advair Diskus (fluticasone propionate and salmeterol xinafoate) [4/2016 version]
• Advair HFA (fluticasone propionate and salmeterol xinafoate) [2/2017 version]
• Afrezza (insulin human) [2015 version]
• Ambien (zolpidem tartrate) [2014 version]
• Ambien CR (zolpidem tartrate) [2014 version]
• Amevive* (alefacept) [2012 version]
• Amjevita (adalimumab-atto) [9/2016 version]  
• Ampyra (dalfampridine) [2016 version]  
• Anafranil (clomipramine hydrochloride) [2014 version]
• Anaprox (naproxen sodium) [8/2016 version]
• Androgel (1%) (testosterone) [2014 version] 
• Androgel (1.62%) (testosterone) [2015 version]
• Anoro Ellipta (Umeclidinium; Vilanterol) [3/2017 version]
• Ansaid (flurbiprofen) [5/2016 version]
• Aplenzin (bupropion hydrobromide [5/2017 version]
• Aptryxol( desvenlafaxine ) extended Release Tablets  [2017 version]
• Aranesp* (darbepoetin alfa) [4/2017 version)

• Arcapta (indacaterol maleate) [2012 version]

• Aristada (aripiprazole lauroxil) [10/2015 version]

• Arthrotec (diclofenac sodium) [5/2016 version]
• Arymo ER (morphine sulfate)  [2017 version]
• Astagraf XL (tacrolimus) [2014 version]
• Atelvia (risedronate sodium) [2015 version]
• Ativan (lorazepam) [2016 version]
• Aubagio (teriflunomide) [2016 version]
• Austedo (deutetrabenazine ) [4/2017 version]
• Avandamet (metformin hydrochloride and rosiglitazone maleate) [4/2017 version]
• Avandaryl (glimepiride and rosiglitazone maleate) [3/2015 version]
• Avandia (rosiglitazone maleate) [5/2014 version]
• Aveed (testosterone undecanoate) [5/2015 version]
• Avelox (moxifloxacin) [7/2016 version] 
• Avinza (morphine sulfate) [2014 version]
• Avonex* (interferon beta-1a) [2014 version]
• Axiron (testosterone) [2017 version]
• Banzel (rufinamide) [2015 version]
• Bavencio (avelumab) [5/2017 version]
• Belbuca (buprenorphine) [12/2016 version]
• Belsomra  (suvorexant) [2014 version]
• Benlysta (belimumab) [2016 version] 
• Betaseron*(interferon beta-1b) [2016 version]
• Bevespi Aerosphere (glycopyrrolate and formoterol fumarate) [4/2016 version]
• Binosto (alendronate sodium) [2/2015 version]
• Blincyto (blinatumomab) injection [5/2017 version] 
• Boniva (ibandronate sodium) Injection [2016 version]
• Boniva (ibandronate sodium) Tablets [2016  version]
• Botox* (onabotulinumtoxinA) [1/2016 version]
• Breo Ellipta (fluticasone furoate and vilanterol) [5/2017 version]
• Brilinta (ticagrelor) [9/2016 version]
• Brintellix (vortioxetine) [2014 version] 
• Brisdelle (paroxetine) [4/2017 version]
• Briviact ((brivaracetam) [2/2016 version]
• Brovana (arformoterol tartrate) [2014 version]
• Bunavail (Buprenorphine and naloxone) Buccal Film (2016)
• Butrans (buprenorphine) [2016 version] 
• Bydureon (exenatide) [32015 version]
• Byetta (exenatide) [2/2015 version]
• Cambia (diclofenac) [3/2017 version]
• Caprelsa (vandetanib) [3/2014 version]
• Carbatrol (carbamazepine) [2013 version]
• Cataflam (diclofenac potassium) [5/2016 version]
• Celebrex (celecoxib) [5/2016 version]
• Celexa (citalopram hydrobromide) [2017version]
• Cellcept (mycophenolate mofetil) [2013 version] 
• Celontin (methsuximide) [2010 version]
• Cerdelga (eliglustat) [2014 version]
• Chantix (varenicline tartrate) [2016 version]
• Cimzia* (certolizumab pegol) [2016 version]
• Cipro (ciprofloxacin) [2016 version]
• Clinoril (sulindac) [2010 version]
• Codeine Sulfate oral solution [2016 version]
• Codeine Sulfate tablets [2016 version]
• Colcrys (colchicine) [2012 version]
• Combunox (oxycodone hydrochloride and ibuprofen) [2010 version]
• Concerta (methylphenidate hydrochloride) [2013 version]
• Contrave(naltrexone HCl and bupropion HCl) ER [5/2017 version]
• Copegus (ribavirin) [2015 version]
• Cordarone (amiodarone hydrochloride) [3/2015 version]
• Corlanor (ivabradine) [2017 version]
• Cosentyx (secukinumab) [2015 version]
• Coumadin (warfarin sodium) [2016 version]
• Creon (pancrelipase) [2012 version]
• Cymbalta (duloxetine hydrochloride) [2017 version)]

• Daliresp (roflumilast) [2015 version]

• Dalmane (flurazepam hydrochloride) [2009 version]
• Darvocet (acetaminophen and propoxyphene napsylate) [2009 version]
• Darvon (propoxyphene hydrochloride) [2009 version]
• Daypro (oxaprozin potassium) [5/2016 version]
• Daypro Alta (oxaprozin potassium) [5/2016 version]
• Daytrana (methylphenidate) [2017 version] 
• Depakene (valproic acid) [3/2017 version] 
• Depakote ER(divalproex sodium) [3/2017 version]
• Desoxyn (methamphetamine hydrochloride) [2015 version]
• Desvenlafaxine Extended Release Tablet(desvenlafaxine fumarate) [2017version] 
• Dexedrine (dextroamphetamine sulfate) [2013 version]
• Dexilant (dexlansoprazole) [2016 version]
• Dilantin (phenytoin) Chewable/ER [2015 version]
• Dilantin-125 (phenytoin) [2016 version]
• Dolophine (methadone hydrochloride) [2016 version]
• Doral (quazepam) [2016 version]
• Duetact (glimepiride and pioglitazone) [3/2015 version]
• Duexis (ibuprofen and famotidine) [5/2016 version]
• Dulera (mometasone furoate and formoterol fumarate) [4/2015 version]
• Duragesic (fentanyl) [2016 version]
• Dyanavel XR (amphetamine) [5/2017 version]
• Dysport* (abobotulinumtoxinA) [2016 version]
• EC-Naprosyn (naproxen) [8/2016 version]
• Edluar (zolpidem tartrate) [2013 version]
• Effexor (venlafaxine hydrochloride) [2012 version]
• Effexor XR (venlafaxine hydrochloride) [1/2017 version
• Effient (prasugrel) [1/2016 version]
• Elidel Cream (pimecrolimus) [3/2014 version]
• Eliquis (apixaban) [6/2015 version]
• Embeda (morphine sulfate and naltrexone hydrochloride) [2014 version]
• Emsam (selegeline transdermal system) [2007 version]
• Enbrel* (etanercept) [2013 version]
• Entyvio (vedolizumab) [2014 version]  
• Epogen* (epoetin alfa) [2012 version] 
• Epzicom (abacavir sulfate and lamivudine) [3/2017 version]
• Equetro (carbamazepine) [9/2016 version]
• Erivedge (vismodegib) [2016 version] 
• Estazolam [2008 version]
• Evista (raloxifene hydrochloride) [2007 version]
• Exalgo (hydromorphone hydrochloride) [2014 version]
• Extavia (interferon beta-1b) [2016 version]
• Extraneal (icodextrin) [2010 version]
• Exubera (insulin recombinant human) [2008 version]
• Factive (gemifloxacin) [2016 version]
• Farxiga (dapagliflozin) [8/2016 version]
• Farydak (panobinostat) [2/2015 version]

• Felbatol (felbamate) [2011 version]

• Feldene (piroxicam) [5/2016 version]
• Fentora (fentanyl citrate) [12/2016 version]
• Ferriprox (deferiprone) [2012 version]
• Fetzima (levomilnacipran) [2017 version]
• FIORINAL with CODEINE (Butalbital, Aspirin, Caffeine, and Codeine Phosphate) [12/2016 version]
• Flector (diclofenac epolamine) [5/2016 version]
• Floxin (ofloxacin) [2011 version]
• Fluoxetine (Fluoxetine) [2017 version]
• Fluvoxamine (Fluvoxamine Maleate) [2014 version]
• Focalin (dexmethylphenidate hydrochloride) [2017 version]
• Focalin XR (dexmethylphenidate hydrochloride) [2017 version]
• Foradil Aerolizer (formoterol fumarate inhalation powder) [2012 version]
• Foradil Certihaler (formoterol fumarate inhalation powder) [2010 version]
• Forfivo XL (bupropion hydrochloride) [5/2017 version]
• Forteo (teriparatide) [2013 version]
• Fortesta (testosterone) [5/2015 version]
• Fosamax (alendronate sodium) [2013 version]
• Fosamax Plus D (alendronate sodium and cholecalciferol) [2013 version]
• Fosrenol (lanthanum carbonate) [9/2014 version]
• Fycompa (perampanel) [4/2016 version] 
• Gabitril (tiagabine) [11/2015 version]
• Gattex (teduglutide [rDNA origin]) [2012 version] 
• Gilenya (fingolimid) [2/2016 version]
• Glyxambi (empagliflozin and linagliptin) Tablets [3/2017 version]
• GoLytely (polyethylene glycol 3500, potassium chloride, sodium bicarbonate, sodium chloride, and sodium sulfate anhydrous) [2013 version]
• Gralise (gabapentin) [2012 version]
• Halcion (triazolam) [2016 version]
• HalfLytely and Bisacodyl Bowel Prep Kit (bisacodyl, polyethylene glycol 3500, potassium chloride, sodium bicarbonate, and sodium chloride) [2010 version]
• Horizant (gabapentin enacarbil) [2013 version] 
• H.P. Acthar Gel (repository corticotropin) [2010 version]
• Humira (adalimumab) [4/2017 version]
• Hycodan ( hydrocodone bitartrate and homatropine methylbromide) [2017 version]
• Hydromorphone Hydrochloride ER [2014 version]
• Hysingla ER (Hydrocodone, Bitartrate) [2016 version]
• Iclusig (ponatinib) [2016 version]
• Ilaris* (canakinumab) [7/2016 version]
• Imfinzi (durvalumab) [4/2017 version]
• Impavido (miltefosine) [2014 version]
• Incivek (telaprevir) [2013 version]
• Indocin (indomethacin) [5/2016 version]
• Indocin SR (indomethacin) [5/2016 version]
• Inflectra (Infliximab-dyyb) [4/2016 version]
• Infergen* (interferon alfacon-1) [2013 version]
• Intermezzo (zolpidem tartrate) [2013 version]
•  Intron A* (interferon alfa-2b) [4/2014 version]
• Invirase (saquinavir mesylate) [12/2016 version] 
• Invokamet (canagliflozin and metformin hydrochloride) [2017]  
• Invokamet XR (canagliflozin and metformin hydrochloride extended-release) [2016 version]
• Invokana (canagliflozin) [2016 version]
• Janumet (metformin hydrochloride and sitagliptin phosphate) [2013 version]
• Janumet XR (sitagliptin and metformin hydrochloride) [2014 version]
• Januvia (sitagliptin phosphate) [2013 version]
• Jentadueto (linagliptin and metformin hydrochloride) [3/2017 version]
• Jentadueto XR (linagliptin and metformin hydrochloride) [7/2017 version] 
• Juvisync (sitagliptin and simvastatin) [2014 version]
• Juxtapid (lomitapide) [5/2016 version]   
• Kadian (morphine sulfate) [12/2016 version]
• Kalbitor* (ecallantide) [3/2014 version]
• Kaletra Capsules (lopinavir and ritonavir) [2013 version]
• Kaletra Tablets and Oral Solution (lopinavir and ritonavir) [11/2016 version]  
• Kazano (alogliptin and metformin hydrochloride) [4/2016 version] 
• Keppra (levetiracetam) [4/2017 version]
• Keppra XR (levetiracetam) [4/2017 version
• Ketek (telithromycin) [2010 version]
• Keytruda (pembrolizumab) [5/2017 version]
• Khedezla (desvenlafaxine) [2016 version]
• Klonopin (clonazepam) [2016 version] 
• Kombiglyze XR (metformin hydrochloride and saxagliptin) [2/2017 version]  
• Korlym (mifepristone) [5/2017 version]
• Krystexxa* (pegloticase) [12/2014 version]
• Kynamro (mipomersen sodium) [5/2016 version] 
• Lacosamide Tablets (lacosamide) [4/2016 version]
• Lacosamide Tablets CV (lacosamide) [4/2016 version]
• Lacosamide Oral Solution (lacosamide) [3/2016 version]
• Lamictal (lamotrigine) [2013 version] 
• Lamictal XR (lamotrigine) [2013 version]
• Lamisil (terbinafine hydrochloride) [8/2016 version]
• Lariam (mefloquine hydrochloride) [2009 version]
• Latuda (lurasidone hydrochloride) [2017 version]
• Lazanda (fentanyl citrate) [2016 version]
• Lemtrada (alemtuzumab) Injection [11/2014 version]
• Letairis (ambrisentan) [10/2015 version] 
• Levaquin (levofloxacin) [2016 version]
• Lexapro (escitalopram oxalate) [2017 version]
• Librax  ( chlordiazepoxide HCl and clidinium bromide ) [2017 version]
• Librium(chlordiazepoxide) [2016 version]
• Limbitrol (chlordiazepoxide and amitriptyline) [2016 version]
• Lindane Lotion (lindane) [2007 version]
• Lindane Shampoo (lindane) [2007 version]
• Linzess (linaclotide) [3/2017 version]
• Lotronex (alosetron hydrochloride) [/2016 version]
• Lunesta (eszopiclone) [2014 version]
• Lupron Injection (leuprolide acetate) [5/2017 version]
• Lupron Depot-Ped (leuprolide acetate for depot suspension) [5/2017 version]
• Luvox (fluvoxamine maleate) [2014 version] See: Fluvoxamine
• Luvox CR (fluvoxamine maleate) [2014 version]
• Lynparza (olaparib) [2014 version]
• Lyrica (pregabalin) [2013 version]
• Marplan (isocarboxazid) [2008 version]
• Mekinist (trametinib) [2015 version]
• Meridia (sibutramine hydrochloride) [2010 version]
• Metadate CD (methylphenidate hydrochloride) [2014 version]
• Methylin (methylphenidate)
  • chewable tablets [2013 version]
  • oral solution [2013 version]
• Metoclopramide Oral Solution [2009 version]
• Metozolv ODT (metoclopramide hydrochloride) [2011 version]
• Mifeprex (mifepristone) [2016 version]
• Mircera* (methoxy polyethylene glycol-epoetin beta) [4/2016 version]
• Mitigare (Colchicine) [9/2014 version]
• Mobic (meloxicam) [5/2016 version]
• Morphabond (morphine sulfate)extended release tablets [12/2016]
• Morphine Sulfate (morphine sulfate oral solution) [2011 version]
• Motrin (ibuprofen) [2007 version]

• Moviprep (polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid) [2013 version]

• Moxifloxacin (moxifloxacin) [7/2016 version]

• MS Contin (morphine sulfate) [2014 version] 

• Multaq (dronedarone) [2014 version]
• Myalept (Metreleptin) [2015 version]
• Myfortic (mycophenolic acid) [2013 version]
• Myobloc* (rimabotulinumtoxinB) [2009 version]
• Mysoline (primidone) [2010 version]

• Nalfon (fenoprofen calcium) [5/2016 version]
• Naprelan (naproxen sodium) [2011 version]
• Naprosyn (naproxen) [3/2017 version]
• Nardil (phenelzine sulfate) [2007 version]
• Natpara (parathyroid hormone) for injection [12/2015 version]
• Nesina (alogliptin) [4/2016 version]
• Neurontin (gabapentin) [9/2015 version]
• Nexium (esomeprazole magnesium) [3/2014 version] 
• Nizoral (ketoconazole) [2014 version]
• Noctiva (desmopressin acetate) [3/2017 version]
• Nolvadex (tamoxifen) [2006 version]
• Noroxin (norfloxacin) [2016 version]
• Norpramin (desipramine hydrochloride) [2014 version]
• Novantrone (mitoXantrone) [2012 version]
• Nplate* (romiplostim) [4/2016 version]
• NSAID (Nonsteroidal Anti-inflammatory Drugs) [8/2016 version]
• Nucynta (tapentadol hydrochloride) [11/2016 version]
• Nucynta ER (tapentadol) [2014 version]
• Nulojix (belatacept) [2014 version]
• NuLytely (polyethylene glycol 3500, potassium chloride, sodium bicarbonate, and sodium chloride) [2013 version]
• Nuvigil (armodafinil) [4/2015 version]
• Ocrevus (ocrelizumab) [3/2017 version]
• Obredon (hydrocodone bitartrate and guaifenesin) [2017 version]
• Odomzo (sonidegib) [2015]
• Oleptro (trazodone hydrochloride) [2014 version]
• Omontys (peginesatide) [2012 version]
• Onfi (clobazam) [2016 version]
• Onglyza (saxagliptin hydrochloride) [2/2017 version]
• Onsolis (fentanyl buccal soluble film) [2016 version]
• Opana ER (oxymorphone hydrochloride) [2016 version]
• Opdivo (nivolumab) [4/2017 version]
• Opsumit (macitentan) [3/2017 version]
• Oseni (alogliptin and pioglitazone) [12/2016 version] 
• Osmoprep (sodium phosphate dibasic anhydrous and sodium phosphate monobasic monohydrate) [2012 version]
• OXAYDO (oxycodone HCl) [2016 version]
• Oxtellar XR (oxcarbazepine) [2012 version]
• Oxycodone Hydrochloride Capsules [2016 version]
• Oxycodone Hydrochloride Oral Solution [2013 version]
• OxyContin (oxycodone hydrochloride) [2015 version]
• Oxymorphone Hydrochloride [1/2015 version]
• Pacerone (amiodarone hydrochloride) [2008 version]
• Palladone (hydromorphone hydrochloride) [2004 version]
• Pamelor (nortriptyline hydrochloride) [2012 version]
• Pancreaze (pancrelipase) [2014 version]
• Parnate (tranylcypromine sulfate) [2008 version]
• Paxil (paroxetine hydrochloride) [2014 version]
• Paxil CR (paroxetine hydrochloride) [2014 version]
• Peganone (ethotoin) [2010 version]
• Pegasys* (peginterferon alfa-2a) [2014 version]
• Pegintron* (peginterferon alfa-2b) [2013 version] 
• PegIntron*/Rebetol Combo Pack (peginterferon alfa-2b and ribavirin) [2008 version]
• Pennsaid (diclofenac sodium) [5/2016 version]
• Percodan (ASPIRIN; OXYCODONE HYDROCHLORIDE; OXYCODONE TEREPHTHALATE) [2016 version]
• Perforomist (formoterol fumarate) [2012 version]
• Pertzye (pancrelipase) [2012 version]
• Pexeva (paroxetine mesylate) [2017 version]
• Plavix (clopidogrel bisulfate) [9/2016 version]
• Plegridy (peginterferon beta-1a) [7/2016 version]
• Pomalyst (pomalidomide) [4/2015 version]
• Ponstel (mefenamic acid) [5/2016 version]
• Potiga (ezogabine) [5/2016 version]
• Pradaxa (dabigatran etexilate mesylate) [2015 version] 
• Prepopik (sodium picosulfate, magnesium oxide and citric acid) [2012 version]
• Prevacid (lansoprazole [12/2015 version]
• Prevacid NapraPac (lansoprazole and naproxen) [5/2019 version]
• Priftin (rifapentine) Tablets [11/2014 version]
• Prilosec (omeprazole [2016 version]
• Pristiq (desvenlafaxine succinate) [2017 version]
• Procrit (epoetin alfa) [4/2017 version]
• Prolia* (denosumab) [2/2015 version] 
• Promethazine HCl and Codeine Phosphate (2017 version)
• Promethazine Hydrochloride, Phenylephrine Hydrochloride and Codeine Phosphate (2017 version)
• Propylthiouracil [2010 version]
• Promacta (eltrombopag) [3/2017version]
• Propulsid (cisapride) [2006 version]
• Proquin XR (ciprofloxacin hydrochloride) [2011 version]
• Protonix (pantoprazole sodium) [2013 version]
• Protopic Ointment (tacrolimus) [2011 version]
• Provigil (modafinil) [2015 version]
• Prozac (fluoxetine hydrochloride) [2017 version]
• Qsymia (phentermine and topiramate) [9/2014 version]
• Qtern (dapagliflozin and saxagliptin) [2/2017 version]
• Qualaquin (quinine sulfate) [2014 version]
• Qudexy XR (topiramate) [2017? version]
• QuilliChew ER (methylphenidate Hydorchloride) [3/2017 version]
• Quillivant XR (methylphenidate) [2015 version] 
• Rapamune (sirolimus) [5/2015 version]
• Ravicti (glycerol phenylbutyrate) [4/2017 version]
• Rebetol (ribavirin) [2013 version]
• Rebif* (interferon beta-1a) [4/2014 version]
• Reclast (zoledronic acid) [1/2015 version]
• Reglan (metoclopramide hydrochloride) injection [2009 version] 
• Reglan (metoclopramide hydrochloride) tablets [2011 version]
• Reglan ODT (metoclopramide hydrochloride) [2011 version]
• Relistor (methylnaltrexone bromide) [9/2014 version]
• Remeron (mirtazapine) [2014 version]
• Remeron SolTab (mirtazapine) [2014 version]
• Remicade* (infliximab) [10/2015 version]
• Renflexis (infliximab-abda) [4/2017 version]
• Restoril (temazepam) [2016 version]
• Revlimid (lenalidomide) [2017 version]
• Rexulti  (brexpiprazole) [8/2015 version] 
• Rezira ( hydrocodone bitartrate and pseudoephedrine hydrochloride) [2017 version] 
• Ribasphere (ribavirin) [2008 version]
• Ritalin (methylphenidate hydrochloride) [2015 version]
• Ritalin LA (methylphenidate hydrochloride) [2017version]
• Ritalin-SR (methylphenidate hydrochloride) [2017 version]
• Rituxan* (rituximab) [2013 version]
• Roferon-A* (interferon alfa-2a recombinant) [2008 version]
• Roxocodone (oxycodone hydrochloride ) [12/2016 version]
• Roxybond (oxycodone hydrochloride) [4/2017 version]
• Rozerem (ramelteon) [2010 version]
• Sabril (vigabatrin) [4/2017 version] 
• Samsca (tolvaptan) [2014 version]
• Sarafem (fluoxetine hydrochloride) [2017 version]
• Savaysa (edoxaban) tablets [2015 version]
• Savella (milnacipran hydrochloride) [8/2016 version]
• Saxenda (liraglutide) injection [9/2016 version]
• Selzentry (maraviroc) [3/2014 version] 
• Serevent Diskus (salmeterol xinafoate) [4/2014 version]
• Seroquel (quetiapine fumarate) [2013 version] 
• Seroquel XR (quetiapine fumarate) [2013 version] 
• Signifor (pasireotide diaspartate) [3/2015 version] 
• Silenor (doxepin) [2010 version]
• Siliq (brodalumab) [2017version]
• Simponi (golimumab) [2016 version]
• Simponi Aria (golimumab) [2016 version]
• Sinequan (doxepin hydrochloride) [2007 version]
• Sirturo (bedaquiline) [2013 version] 
• Sodium Oxybate [2016 version]
• Solaraze (diclofenac sodium) Gel, 3% [5/2016 version]
• Soliqua (insulin glargine and lixisenatide) [2016 version]
• Soliris* (eculizumab) [2017 version]
• Soltamox (tamoxifen citrate) [2005 version]
• Sonata (zaleplon) [2013 version]
• Soriatane (acitretin) [2014 version]
• Sotret (isotretinoin) [2006 version]
• SPRIX (ketorolac tromethamine) Nasal Spray [5/2016 version]
• Spritam (levetiracetam) tablets [2/2016 version]
• Stavzor (valproic acid) [2013 version]
• Stelara* (ustekinumab) [9/2016 version]
• Stiolto Respimat (tiotropium bromide and olodaterol) [2016 version]
• Strattera (atomoxetine hydrochloride) [2014 version] 
• Striverdi respimat (olodaterol) [2016 version]
• Suboxone (buprenorphine and naloxone) [12/2016 version] 
• Subsys (fentanyl) [2016 version]
• Subutex (buprenorphine) [2016 version]
• Suclear (sodium sulfate, potassium sulfate, magnesium sulfate, sodium chloride, sodium bicarbonate, and potassium chloride) [2013 version] 
• Suprep (sodium sulfate, potassium sulfate and magnesium sulfate) [2010 version]
• Supprelin LA (histrelin acetate) [5/2017 version]
• Surmontil (trimipramine) [2014 version]
• Sustol ( granisetron) [8/2016 version] 
• Sutent (sunitimib malate) [2013 version]
• Sylatron (peginterferon alfa-2b) [5/2015 version]
• Symbicort (budesonide and formoterol fumarate dihydrate) [2017 version]
• Symbyax (fluoxetine hydrochloride and olanzapine) [2017 version]
• Symlin (pramlintide acetate) [2007 version]
• Synalgos-DC (aspirin, caffeine, and dihydrocodeine bitartrate) [2016 version]
• Synarel (nafarelin acetate) [2017 version]
• Synjardy (empagliflozin and metformin hydrochloride) [2016]
• Synjardy XR (empagliflozin and metformin Hydrochloride Extended Release) [2016 version]
• Synribo (omacetaxine mepesuccinate) [4/2014 version]
• Tafinlar (dabrafenib) [2013 version] 
• Taltz (ixekizumab) [3/2016]
• Tanzeum (albiglutide) [3/2015 version]
• Tapentadol see Nucynta 
• Targiniq ER (oxycodone hydrochloride and naloxone hydrochloride extended-release tablets) [2016 version]
• Tasigna (nilotinib) [2/2017 version] 
• Tecentriq (atezolizumab) [4/2017version] 
• Technivie (ombitasvir, paritaprevir and ritonavir tablets) [3/2017 version]
• Tegretol and Tegretol XR (carbamazepine) [2014 version]
• Testim (testosterone) [5/2015 version]
• Testosterone Gel (Perrigo) [5/2015 version]
• Testosterone Gel (Teva) [5/2015 version]
• Thalomid (thalidomide) [2017 version]
• Tikosyn (dofetilide) [2013 version]
• Tivorbex  (indomethacin) [5/2016 version]
• Tofranil (imipramine hydrochloride) [2007 version]
• Tofranil-PM (imipramine pamoate) [2012 version]
• Tolectin (tolmetin sodium) [2008 version]
• Topamax (topiramate) [3/2014 version]
• Toradol (ketorolac tromethamine) [2013 version]
• Tracleer (bosentan) [12/2015 version]
• Tradjenta (linagliptin) [3/2017 version]
• Tranxene (clorazepate dipotassium) [2016 version]
• Trazodone (Trazodone Hydrochloride) [2014 version]
• Treximet (naproxen sodium and sumatriptan succinate) [5/2016 version]
• Tridione (trimethadione) [2012 version]
• Trileptal (oxcarbazepine) [2011 version]
• Trilipix (choline fenofibrate) [2012 version]
• Trintellix (vortioxetine) [4/2017 version]
• Triumeq (abacavir, dolutegravir, and lamivudine) tablets [3/2017version]
• Trizivir (abacavir sulfate, lamivudine and zidovudine) [3/2017 version]
• Troxyca (oxycodone hydrochloride and naltrexone hydrochloride) [2016 version]
• Trokendi XR (topiramate) [4/2017 version]
• Trulicity (dulaglutide) [2017 version]
• Truvada (emtricitabine and tenofovir disoproxil fumarate) [4/2017 version]
• Tussionex (hydrocodone polistirex and chlorpheniramine polistirex) [2017 version]
• Tuxarin ER ( codeine phosphate and chlorpheniramine maleate ) [2017 verion]
• Tuzistra XR  (codeine polistirex and chlorpheniramine polistirex) [2017 version]
• Tysabri (natalizumab) [5/2015 version]
• Tyzeka (telbivudine) [2013 version]
• Ultracet ( tramadol  hydrochloride/acetaminophen) [2016 version] 
• Ultresa (pancrelipase) [2012 version]
• Ultram(tramadol hydrochloride) 2[016 version]
• Ultram ER (tramadol hydrochloride extended-release tablets [2016 version]
• Valchlor (mechlorethamine) [2013 version]
• Valium (diazepam) [2016 version]
• Vandetanib see Caprelsa
• Vantrela ER ( hydrocodone bitartrate) [2017 version]
• Venclexta (venetoclax) [4/2016 version]
• Venlafaxine HCl ER (venlafaxine hydrochloride) [2017 version]
• Vibativ (telavancin) [12/2014 version]
• Viberzi  (eluxadoline) [4/2017 version]
• Vicoprofen (hydrocodone bitartrate and ibuprofen) [2016 version]
• Victoza (liraglutide) [5/2016 version]
• Victrelis (boceprevir) [2014 version]
• Videx (didanosine) [2011 version]
• Videx EC (didanosine) [2011 version]
• Viekira Pak ((ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) [3/2017 version]
• Viekira XR  (dasabuvir, ombitasvir, paritaprevir, and ritonavir) [3/2017 version] 
• Viibryd (vilazodone hydrochloride) [2017 version] 
• Vimovo (esomeprazole magnesium and naproxen) [5/2016 version]
• Vimpat (lacosamide) [8/2014 version] 
• Viokace (pancrelipase) [2012 version]  
• Viramune and Viramune XR (nevirapine) [3/2017 version] 
• Visicol (sodium phosphate dybasic anhydrous and sodium phosphate monobasic monohydrate) [2013 version]
• Vituz ( hydrocodone bitartrate and chlorpheniramine maleate) [2017 version]
• Vivactil (protriptyline hydrochloride) [2007 version]
• Vivitrol (naltrexone) [2013 version]
• Vogelxo (testosterone) gel [5/2015 version]
• Voltaren (diclofenac sodium) [5/2016 version]
• Voltaren XR (diclofenac sodium) [5/2016 version]
• Votrient (pazopanib hydrochloride) [5/2016 version]
• Vyvanse (lisdexamfetamine dimesylate) [2017 version]
• Wellbutrin (bupropion hydrochloride) [5/2017 version]
• Wellbutrin SR (bupropion hydrochloride) [5/2017 version]
• Wellbutrin XL (buproprion hydrochloride) [5/2017 version] 
• Xanax (alprazolam) [2016 version]
• Xanax XR (alprazolam) [2016 version]
• Xarelto (rivaroxaban) [5/ 2016 version]
• Xartemis XR (oxycodone hydrochloride and acetaminophen) [12/2016 version]
• Xeljanz (tofacitinib) [3/2014 version]
• Xenazine (tetrabenazine) [6/2015 version]
• Xeomin* (incobotulinumtoxinA) [2011 version]
• Xiaflex* (collagenase clostridium histolyticum) [8/2016 version] 
• Xigduo XR ( Depagliflozin and Metformin HCL extended release ) [8/2016 version] 
• Xolair* (omalizumab) [7/2016 version]
• Xtampza ER (oxycodone) [2016 version]
• Xultophy (insulin degludec and liraglutide injection) [11/2016 version] 
• Xyrem (sodium oxybate) [2015 version]
• Yervoy* (ipilimumab) [12/2013 version]
• Yosprala (aspirin and omeprazole) [ 9/2016 version ] 
• Zarontin (ethosuximide) [2012 version]
• Zegerid (omeprazole and sodium bicarbonate) [2014 version]
• Zelboraf (vemurafenib) [8/2016 version] 
• Zenpep (pancrelipase) [2014 version]
• Zerit (stavudine) [2011 version]
• Ziagen (abacavir sulfate) [3/2017 version]
• Zinbryta (daclizumab) [2016 version]
• Zipsor (diclofenac potassium) [5/2016 version]
• Zohydro ER (hydrocodone bitartrate) [2016 version]
• Zoloft (sertraline hydrochloride) [2016 version]
• Zolpidem (zolpidem tartrate) [2008 version] 
• Zolpimist (zolpidem tartrate) [2008 version]
• Zonegran (zonisamide) [4/2016 version]
• Zontivity (vorapaxar) [2013 version]
• Zortress (everolimus) [2013 version]
• Zorvolex (diclofenac) [5/2016 version]
• Zubsolv (buprenorphine and naloxone) [2013 version] 
• Zurampic (lesinurad) [2016 version]
• Zutripro ((hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride ) [2017 version]
• Zyban (bupropion hydrochloride) [5/2017 version]
• Zydelig ( idelalisib) [9/2016 version] 
• Zyprexa (olanzapine) [2013 version]
• Zyprexa Relprevv (olanzapine) [2012 version]

Safe Antibiotics During Pregnancy : Amoxicillin Ampicillin Clindamycin Erythromycin Penicillin Gentamicin Ampicillin-Sulbactam Cefoxitin Cefotetan Cefazolin

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

The Food and Drug Administration lists antibiotics in categories based on safety for use during pregnancy. It has established five categories to indicate the evidence and the potential of a drug to cause birth defects if used during pregnancy. The categories are determined by the reliability of documentation and the risk to benefit ratio. They do not take into account any risks from pharmaceutical agents or their metabolites in breast milk. 

The categories are:  The categories are A, B, C, D and X.

CATEGORY DEFINITION COMMENTS A Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities. Drugs that fall under category A have had several well-controlled studies that found no harmful effects or increase in birth defects. These drugs have all had studies conducted in pregnant woman with positive results. Very few drugs fall into this category. Prenatal vitamins receive a category A rating. B Animal studies have revealed no evidence of harm to the fetus, however there are no adequate and well-controlled studies in pregnant women or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. Drugs assigned a category B rating are not likely to pose a threat to the fetus from the evidence in animal studies, but no well-controlled studies have been performed in pregnant women. However, a drug may also receive a category B rating if animal studies have shown evidence of fetus damage but the same drug tested on pregnant women posed no threat. C

Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women. Or, no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.

A category C rating is given to drugs that have been shown to be harmful in animal studies but no studies have been conducted on pregnant humans. Drugs may also receive a category C rating if the drug was not studied in animals and there isn't enough evidence from studies in pregnant humans. This implies that the drug may or may not be safe to take.

D Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.

Drugs receive a category D rating when the drugs have been tested in well-controlled or observational (not controlled) studies, which resulted in harm to the unborn baby. In some cases these drugs may still be given if the benefits to the mother outweigh the risks to the baby (for example, cancer treatment).

X

Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant.

A Category X rating is assigned to drugs that should never be used during pregnancy, as there are no benefits that would exceed the potential risk.

Using Antibiotics During Pregnancy

According to doctors and researchers, a few guidelines should be followed before prescribing an antibiotic to a pregnant patient. These include:

    Only use antibiotics if no other treatment option will suffice.
    Avoid prescribing antibiotics during the first trimester when possible.
    Choose a safe medication (typically an older antibiotic tested on pregnant women).
    Choose single prescriptions over polypharmacy when possible.
    Dose at the lowest possible amount proven effective.
    Advise patients not to use over the counter medications during antibiotic treatment.

Antibiotics Generally Considered Safe for Use During Pregnancy

Some of the common infections during pregnancy that require antibiotic treatment include urinary tract infection, bladder infection, pyelonephritis and appendicitis. This is not a complete list of infections that require antibiotic treatment.

If your physician prescribes an antibiotic for use during pregnancy, it is extremely likely that the drug falls into either Category A or Category B on the FDA list of approved drugs for use during pregnancy. Some of the antibiotics that may be prescribed safely during pregnancy include:

    Amoxicillin
    Ampicillin
    Clindamycin
    Erythromycin
    Penicillin
    Gentamicin
    Ampicillin-Sulbactam
    Cefoxitin
    Cefotetan
    Cefazolin

Clinical Information and New Antibiotics


There is very little clinical information on the effect of new antibiotics on pregnancy and fetal complication risk. Decades ago, pregnant women were allowed to participate in drug testing so older antibiotics are typically the first prescribed by obstetricians. However, in some cases, despite the lack of formula testing during pregnancy, obstetricians are faced with a risks versus benefits case. If the benefits of prescribing an antibiotic during pregnancy outweigh the potential risks, the antibiotic in question is chosen.

There are several antibiotics safely prescribed during pregnancy. If you have an infection and your obstetrician has prescribed an antibiotic, talk with your doctor about the possible risks of taking the medication. In some cases, as is the case with urinary tract infections, leaving the infection untreated poses a risk to the pregnancy and unborn fetus.

Medicine and Pregnancy

https://www.fda.gov/forconsumers/byaudience/forwomen/ucm118567.htm

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En Español, In Chinese, In French, In French Creole

Are you pregnant and taking medicines?  You are not alone. Many women need to take medicines when they are pregnant. There are about six million pregnancies in the U.S. each year, and 50% of pregnant women say that they take at least one medicine. Some women take medicines for health problems, like diabetes, morning sickness or high blood pressure that can start or get worse when a woman is pregnant. Others take medicines before they realize they are pregnant.

Pregnancy can be an exciting time. However, this time can also make you feel uneasy if you are not sure how your medicines will affect your baby. Not all medicines are safe to take when you are pregnant. Even headache or pain medicine may not be safe during certain times in your pregnancy. 

Here are four (4) tips to help you talk to your healthcare provider about how prescription and over-the-counter medicines might affect you and your baby.

1. Ask Questions

2. Read the Label

3. Be Smart Online

4. Report Problems

Bonus Tip: Help spread the word about pregnancy safety.

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1. Ask Questions.

Always talk to your healthcare provider before you take any medicines, herbs, or vitamins. Don't stop taking your medicines until your healthcare provider says that it is OK.

Use these questions to help you talk to your doctor, nurse, or pharmacist:

• Will I need to change my medicines if I want to get pregnant? Before you get pregnant, work with your healthcare provider to make a plan to help you safely use your medicines.

• How might this medicine affect my baby? Ask about the benefits and risks for you and your baby.

• What medicines and herbs should I avoid? Some drugs can harm your baby during different stages of your pregnancy. At these times, your healthcare provider may have you take something else.

• Will I need to take more or less of my medicine? Your heart and kidneys work harder when you are pregnant. This makes medicines pass through your body faster than usual.

•  Can I keep taking this medicine when I start breastfeeding? Some drugs can get into your breast milk and affect your baby.

• What kind of vitamins should I take? Ask about special vitamins for pregnant women called pre-natal vitamins.

   

Pre-Natal Vitamins

Some dietary supplements may have too much or too little of the vitamins that you need. Talk to your healthcare provider about what kind of pre-natal vitamins you should take.

What is folic acid? Folic acid helps to prevent birth defects of the baby's brain or spine. Ask about how much folic acid you should take before you become pregnant and through the first part of your pregnancy.

 

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2. Read the Label 

 

Check the drug label and other information you get with your medicine to learn about the possible risks for women who are pregnant or breastfeeding. The labeling tells you what is known about how the drugs might affect pregnant women. Your healthcare provider can help you decide if you should take the medicine.

Find information on a specific drug

New Prescription Drug Information

The prescription drug labels are changing. The new labels will replace the old A, B, C, D and X categories with more helpful information about a medicine's risks. The labels will also have more information on whether the medicine gets into breast milk and how it can possibly affect the baby.

 

 

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3. Be Smart Online.

  

Ask your doctor, nurse, or pharmacist about the information you get online. Some websites say that drugs are safe to take during pregnancy, but you should check with your healthcare provider first. Every woman's body is different. It may not be safe for you.

• Do not trust that a product is safe just because it says 'natural'.

• Check with your healthcare provider before you use a product that you heard about in a chat room or group.

 

Online Resources

• CDC - Centers for Disease Control and Prevention

• MotherToBaby

• text4baby

• March of Dimes

   

 

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4. Report Problems.

  

First, tell your healthcare provider about any problems you have with your medicine. Also, tell FDA about any serious problems you have after taking a medicine.

• Call 1-800-FDA-1088 to get a reporting form sent to you by mail.

• Report problems online. 

 

What to Report to FDA

You should report problems like serious side effects, product quality problems and product use errors. Report problems with these products:

• human drugs

• medical devices

• blood products and other biologics (except vaccines)

• medical foods

 Learn more about reporting problems to FDA.

 

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Sign Up for a Pregnancy Registry

Pregnancy Exposure Registries are research studies that get information from women who take prescription medicines or vaccines during pregnancy. Pregnancy registries help women and their doctors learn more about how medicines can be safely used during pregnancy.

• Help other pregnant women. Share your experiences with medicines.

• You will not be asked to take any new medicines.

• You will provide information about your health and your baby's health.

FDA does not run pregnancy registries, but it keeps a list of registries. See if there is a registry for your medicine.

www.fda.gov/pregnancyregistries

 

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Pregnancy Social Media Toolkit

The FDA Office of Women's Health offers resources to help women and healthcare providers get informed about medicines and other products used during pregnancy. Use the Pregnancy Social Media Toolkit to inform pregnant women in your network about medication safety. The toolkit includes resources for pregnant women and health professionals, including sample social media messages and blog posts.

Download and Share: Social Media Toolkit (PDF 166KB)

 

To Learn More

• Get Information about a Specific Drug
• Use of Codeine and Tramadol Products in Breastfeeding Women - Questions and Answers
• Pregnant? Breastfeeding? Better Drug Information Is Coming
• Registries Help Inform Medication Use in Pregnancy
• Pregnancy: A Time for Special Caution
• MotherToBaby - Provides counseling to patients and health care professionals about medicines used during pregnancy and breastfeeding.

Resources for Health Professionals

• Pregnancy and Lactation Labeling Information for Health Professionals
• Pregnancy Registry Information for Health Professionals
• MedWatch
• Treating for Two (CDC)

For Women

Medication Safety for Women ¡Nunca Más! Novelas An Invitation to Collaborate

Free Publications

Take Time to Care Program

Women's Health Topics

Resources for You

• Tips for Pregnant Women
• Get Other FDA Publications for Women
• For Women Homepage
• FDAWomen on Twitter

Page Last Updated: 05/19/2017

Rev Obstet Gynecol.

PMCID: PMC2760892

Antibiotics in Pregnancy: Are They Safe?

Errol R Norwitz, MD, PhD^* and James A Greenberg, MD^†

^*Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT

^†Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Division of Gynecology, Faulkner Hospital, and Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, MA

Author information ▼ Copyright and License information ►

The question of whether to prescribe a course of antibiotics to a pregnant woman is a dilemma faced by obstetrics-gynecology (ob-gyn) care providers on a daily basis. In appropriate circumstances-such as the treatment of asymptomatic bacteriuria to prevent ascending infection and pyelonephritis-related adverse pregnancy outcomes-antibiotic therapy can be both effective and life saving. As with the administration of other medications, the potential benefits need to be weighed against the risk to the fetus. Some antibiotics are known to be teratogenic and should be avoided entirely during pregnancy. These include streptomycin and kanamycin (which may cause hearing loss) and tetracycline (which can lead to weakening, hypoplasia, and discoloration of long bones and teeth). How about other antibiotics? Are they safe? Can they be given with impunity?

A decade ago, a number of well-designed clinical trials^1,2 and systematic reviews³ concluded that broad-spectrum antibiotics can prolong the latency period (interval to delivery) and improve short-term perinatal outcome in pregnancies complicated by preterm premature rupture of membranes (pPROM) prior to 34 weeks of gestation, but not in women with preterm labor and intact membranes. Seven-year follow-up of the fetuses exposed to these antibiotics was recently published.^4,5 Reassuringly, broad-spectrum antibiotics given to fetuses in the setting of pPROM were not associated with any long-term disadvantage, although it is concerning to note that the short-term benefits in perinatal outcome described in the original report¹ did not appear to persist to age 7.⁴ Even more concerning, however, was the observation that fetuses exposed to broad-spectrum antibiotics in the setting of intact membranes were at significantly higher risk of cerebral palsy at age 7 (erythromycin, odds ratio [OR] 1.93; 95% confidence interval [CI], 1.21–3.09; co-amoxiclav, OR 1.69; 95% CI, 1.07–2.67).⁵ The risk was even higher when both antibiotics were given together (4.55% incidence of cerebral palsy compared with 1.97% for co-amoxiclav alone, 2.29% for erythromycin alone, and 1.63% for placebo).⁵ Exposure to co-amoxiclav was also associated with an increased risk of necrotizing enterocolitis.⁵

The mechanism of injury is not clear. The most likely explanation is an antibiotic-mediated suppression of infection and preterm birth, thereby causing the fetus to remain in a hostile proinflammatory intrauterine environment for a longer period of time. However, a direct injurious effect of the antibiotic itself cannot be excluded. Indeed, 1 reason why a significant association between antibiotics and cerebral palsy was observed with intact membranes but not in the setting of pPROM may have to do with the dose and/or duration of antibiotic exposure. Because the vast majority of women in the preterm labor and intact membrane study did not deliver within 48 hours (89.9%) or 7 days (84.6%) of enrollment, their fetuses were more likely to be exposed to the full 10-day course of antibiotic therapy.² In contrast, 30% to 40% of women in the pPROM study delivered within 48 hours and 55% to 60% within 7 days. As such, these fetuses were exposed to antibiotics for a far shorter period of time.¹ An additional adverse effect of the increased use of broad-spectrum antibiotics in the setting of pPROM is an increase in antibiotic resistance, especially erythromycin-resistant Group B β-hemolytic streptococcus (GBS).

The debate about the efficacy and safety of antibiotics in pregnancy must be seen in a larger context. It highlights the philosophical difference between 2 distinct groups of obgyn care providers: those who believe that everything possible should be offered in a given clinical setting in the hope that something will help (also known as the we don't have all the information we need or the might as well give it, it won't do any harm group) and those who hold out against popular opinion until there is consistent and compelling scientific evidence that an individual course of action is beneficial and has a favorable risk-to-benefit ratio (the so-called therapeutic nihilists). As protagonists of the latter camp, we offer the following suggestions to ob-gyn care providers faced with the dilemma of whether to prescribe a medication to a pregnant woman:

• Use medications only if absolutely indicated. For antibiotics, this includes treatment of confirmed infection (urinary tract infection, pyelonephritis, appendicitis, cholecystitis, chorioamnionitis), prevention of ascending infection (asymptomatic bacteriuria), and prevention of early-onset neonatal GBS sepsis.
• If possible, avoid initiating therapy during the first trimester. This is the period of fetal structural development and therefore the highest risk for iatrogenic teratogenicity.
• Select a safe medication, which often means an older drug with a proven track record in pregnancy. Certain antibiotics (streptomycin, kanamycin, tetracycline) are best avoided entirely in pregnancy because of their teratogenicity.
• Wherever possible, single-agent therapy is preferred over polypharmacy. Moreover, narrow-spectrum antibiotics are preferred over those with a broad spectrum for the treatment of established infection and intrapartum GBS chemoprophylaxis. The exception is the use of empiric broad-spectrum antibiotics to prolong latency in the setting of pPROM remote from term (discussed above).
• Use the lowest effective dose.
• Discourage the use of over-the-counter drugs, which may interfere with the efficacy and/or metabolism of prescription medications.

Go to:

References

1. Kenyon SL, Taylor DJ, Tarnow-Mordi W ORACLE Collaborative Group, authors. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE Collaborative Group. Lancet. 2001;357:979–988. [PubMed]

2. Kenyon SL, Taylor DJ, Tarnow-Mordi W ORACLE Collaborative Group, authors. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. ORACLE Collaborative Group. Lancet. 2001;357:989–994. [PubMed]

3. Kenyon S, Boulvain M. Antibiotics for preterm premature rupture of membranes. Cochrane Database Syst Rev. 2000;2 CD001058. [PubMed]

4. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet. 2008;372:1310–1318. [PubMed]

5. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet. 2008;372:1319–1327. [PubMed]

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Articles from Reviews in Obstetrics and Gynecology are provided here courtesy of MedReviews, LLC

Flu-like illness, fever, malaise and chills, followed by severe nonpleuritic chest pain and shortness of breath

Chronic migraine headache and acute shortness of breath associated with nausea, vomiting, diaphoresis and increasing retrosternal chest pain..Increased frequency of his migraine headaches associated with vague retrosternal chest pain and epigastric pain...................................................................................................................Flu-like illness, fever, malaise and chills, followed by severe nonpleuritic chest pain and shortness of breath................................................................................Palpitations, fatigue, vague chest discomfort, and cardiomegaly and pulmonary congestion visible on chest radiograph. He had developed a flu-like illness with low-grade fever, chills, myalgia and headache a week earlier. There had been no preceding cough, hemoptysis, orthopnea, paroxysmal nocturnal dyspnea or ankle edema. .....................................................................................................................................Eosinophilic myocarditis (EM)........................................................................................................Therapeutic effect of anti-IL-5 on eosinophilic myocarditis with large pericardial effusion

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

PROPIONIBACTERIUM ACNES AND CHRONIC DISEASES : P. acnes is an opportunistic pathogen, causing a range of postoperative and device-related infections e.g., surgery,post-neurosurgical infection,joint prostheses, shunts and prosthetic heart valves. P. acnes may play a role in other conditions, including inflammation of the prostate leading to cancer,SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome, sarcoidosis and sciatica.

http://otorhinolaryngology-crete.blogspot.com/2017/05/propionibacterium-acnes-and-chronic.html

P. acnes bacteria live deep within follicles and pores, away from the surface of the skin. In these follicles, P. acnes bacteria use sebum, cellular debris and metabolic byproducts from the surrounding skin tissue as their primary sources of energy and nutrients. Elevated production of sebum by hyperactive sebaceous glands (sebaceous hyperplasia) or blockage of the follicle can cause P. acnes bacteria to grow and multiply.[6]

P. acnes bacteria secrete many proteins, including several digestive enzymes.[7] These enzymes are involved in the digestion of sebum and the acquisition of other nutrients. They can also destabilize the layers of cells that form the walls of the follicle. The cellular damage, metabolic byproducts and bacterial debris produced by the rapid growth of P. acnes in follicles can trigger inflammation.[8] This inflammation can lead to the symptoms associated with some common skin disorders, such as folliculitis and acne vulgaris.[9][10][11]

The damage caused by P. acnes and the associated inflammation make the affected tissue more susceptible to colonization by opportunistic bacteria, such as Staphylococcus aureus. Preliminary research shows healthy pores are only colonized by P. acnes, while unhealthy ones universally include the nonpore-resident Staphylococcus epidermidis, amongst other bacterial contaminants. Whether this is a root causality, just opportunistic and a side effect, or a more complex pathological duality between P. acnes and this particular Staphylococcus species is not known.[12]

P. acnes has also been found in corneal ulcers, and is a common cause of chronic endophthalmitis following cataract surgery. Rarely, it infects heart valves leading to endocarditis, and infections of joints (septic arthritis) have been reported.[5] Furthermore, Propionibacterium species have been found in ventriculostomy insertion sites, and areas subcutaneous to suture sites in patients who have undergone craniotomy. It is a common contaminant in blood and cerebrospinal fluid cultures.

P. acnes has been found in herniated discs.[13] The propionic acid which it secretes creates micro-fractures of the surrounding bone. These micro-fractures are sensitive and it has been found that antibiotics have been helpful in resolving this type of low back pain.[14]

P. acnes can be found in bronchoalveolar lavage of approximately 70% of patients with sarcoidosis and is associated with disease activity, but it can be also found in 23% of controls.[15][16] The subspecies of P. acnes that cause these infections of otherwise sterile tissues (prior to medical procedures), however, are the same subspecies found on the skin of individuals who do not have acne-prone skin, so are likely local contaminants. Moderate to severe acne vulgaris appears to be more often associated with virulent strains.[17]

P. acnes is an opportunistic pathogen, causing a range of postoperative and device-related infections e.g., surgery,[18] post-neurosurgical infection,[19] joint prostheses, shunts and prosthetic heart valves. P. acnes may play a role in other conditions, including inflammation of the prostate leading to cancer,[20] SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome, sarcoidosis and sciatica.[21]

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Dichotic Listening Deficit Associated With Solvent Exposure.Due to their lipophilic nature, solvents can adversely affect large white matter tracks such as the corpus callosum. Previous investigations reveal that long-term workplace exposure to solvents is also deleterious to various auditory processes.

http://otorhinolaryngology-crete.blogspot.com/2017/05/dichotic-listening-deficit-associated.html

Dichotic Listening Deficit Associated With Solvent Exposure.

από Landry, Simon P.; Fuente, Adrian στο Otology & Neurotology Published Ahead-of-Print

Μετάφραση άρθρου

Hypothesis: A significant left ear deficit can be observed in solvent-exposed individuals using the dichotic digit test. Background: Solvents are ubiquitous in global industrial processes. Due to their lipophilic nature, solvents can adversely affect large white matter tracks such as the corpus callosum. Previous investigations reveal that long-term workplace exposure to solvents is also deleterious to various auditory processes. Investigations in exposed populations suggest a decreased performance for dichotic listening. Methods: In this present study, we examined the lateralization of a dichotic digit test score for 49 solvent-exposed individuals along with 49 age- and sex-matched controls. We evaluated group differences between test scores and the right ear advantage using a laterality index (LI). Results: Individual ear results suggest that long-term workplace solvent exposure is associated with a significantly lower dichotic listening score for the left ear. A binaural compound score analysis using a laterality index supports this left-ear deficit. Conclusion: These results provide an insight on the effects of solvent exposure on dichotic listening abilities. Further research should investigate the importance of using dichotic listening tasks to screen for solvent-induced auditory dysfunction in exposed individuals. Copyright (C) 2017 by Otology & Neurotology, Inc. Image copyright (C) 2010 Wolters Kluwer Health/Anatomical Chart Company

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Epstein-Barr virus, human endogenous retroviruses (HERVs) and human herpesvirus 6 (HHV-6) but also less common viruses such as Saffold and measles viruses are associated with multiple sclerosis

http://otorhinolaryngology-crete.blogspot.com/2017/05/epstein-barr-virus-human-endogenous.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Airway management during induction of anaesthesia, spontaneous ventilation (SV) and controlled mechanical ventilation (CMV), using an endotracheal tube (ETT), laryngeal mask (LM), rabbit-specific supraglottic airway device (v-gel) or facemask (FM).

Experimental evaluation of four airway devices in anaesthetized New Zealand White rabbits.

Vet Anaesth Analg. 2017 ;

Authors: Wenger S, Müllhaupt D, Ohlerth S, Prasse S, Klein K, da Silva Valente B, Mosing M

Abstract

OBJECTIVE: To compare airway management during induction of anaesthesia, spontaneous ventilation (SV) and controlled mechanical ventilation (CMV), using an endotracheal tube (ETT), laryngeal mask (LM), rabbit-specific supraglottic airway device (v-gel) or facemask (FM).

STUDY DESIGN: Prospective randomized crossover experiment.

ANIMALS: Ten New Zealand White rabbits.

METHODS: After premedication, rabbits were randomly allocated to four groups: 1) ETT; 2) LM; 3) v-gel or 4) FM. The required dose of propofol, duration and number of attempts to place an airway device and leakage during SV and CMV at different peak inspiratory pressures (6, 10, 12, 14 and 16 cmH2O) were recorded. Computed tomography (CT) of the head, neck and abdomen were performed before and after CMV.

RESULTS: Significantly less propofol and time [2.0±0.5 mg kg(-1), 82±34 seconds, p<0.001] were needed to place the FM compared to the three other groups [v-gel 5.1±2.1 mg kg(-1), 302±124 seconds; LM 4.8±1.2 mg kg(-1), 275±89 seconds; ETT 5.5±1.4 mg kg(-1), 315±147 seconds]. A leak > 25% of the tidal volume occurred at the lowest pressure in FM [median (range), 6 (6-8) cmH2O], which was significantly lower than with v-gel [16 (6-no leak at 16) cmH2O], LM [>16 (6-no leak at 16)] or ETT [>16 (no leak at 16) cmH2O] (p<0.001). On CT images, the height and width of the larynx were significantly smaller with v-gel in comparison to FM and LM (p=0.004). A significant increase in the amount of gas in the stomach (p=0.007), but not gastric volume, was detected in FM and LM.

CONCLUSIONS AND CLINICAL RELEVANCE: The v-gel is a practical alternative to LM and ETT for airway management and CMV, but can compress the larynx. The FM is easily placed, but significant leakage occurs during CMV.

PMID: 28528760 [PubMed - as supplied by publisher]

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Curcumin attenuates lipopolysaccharide/d-galactosamine-induced acute liver injury

Curcumin attenuates lipopolysaccharide/d-galactosamine-induced acute liver injury by activating Nrf2 nuclear translocation and inhibiting NF-kB activation

στο Biomedicine & Pharmacotherapy

Μετάφραση άρθρου

Publication date: July 2017

Source:Biomedicine & Pharmacotherapy, Volume 91

Author(s): Yi-Lian Xie, Jin-Guo Chu, Xiao-Min Jian, Jin-Zhong Dong, Li-Ping Wang, Guo-Xiang Li, Nai-Bin Yang

Curcumin, a polyphenol in curry spice isolated from the rhizome of turmeric, has been reported to possess versatile biological properties including anti-inflammatory, anti-oxidant, antifibrotic, and anticancer activities. In this study, the hepatoprotective effect of curcumin was investigated in lipopolysaccharide (LPS)/d-galactosamine (d-GalN)-induced acute liver injury (ALI) in rats. Experimental ALI was induced with an intraperitoneal (ip) injection of sterile 0.9% sodium chloride (NaCl) solution containing 8μg LPS and 800mg/kg d-GalN. Curcumin was administered once daily starting three days prior to LPS/d-GalN treatment. Results indicated that curcumin could attenuate hepatic pathological damage, decrease serum ALT and AST levels, and reduce malondialdehyde (MDA) content in experimental ALI rats. Moreover, higher dosages of curcumin pretreatment inhibited NF-κB activation and reduced serum TNF-α and liver TNF-α levels induced by LPS/d-GalN ip injection. Furthermore, we found that curcumin up-regulated the expression of nuclear Nrf2 and Nrf2-dependent antioxidant defense genes including heme oxygenase-1 (HO-1), glutamate-cysteine ligase (GCLC), NAD(P)H dehydrogenase, and quinone (NQO-1) in a dose-dependent manner. Our results showed that curcumin protected experimental animals against LPS/d-GalN-induced ALI through activation of Nrf2 nuclear translocation and inhibition of NF-κB activation.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Bottom of an iceberg: undiagnosed aortic aneurysm masquerading as vocal cord palsy

http://otorhinolaryngology-crete.blogspot.com/2017/05/undiagnosed-aortic-aneurysm.html

 από Rao, V. U. S., Chatterjee, S., Swamy, S. S. στο BMJ Case Reports Last 6 Issues Μετάφραση άρθρου Description A previously healthy woman aged 60 years was referred to a tertiary referral cancer centre with change of voice for 1 week suspecting neoplastic aetiology on account of her tobacco chewing habit of more than 20 years. No history of voice abuse, fever or cough was there preceding the onset of the change of voice. She did not have any previous history of hospitalisation or diagnosed comorbidities. On clinical examination, her pulse rate was 82 bpm; blood pressure was 130/90 mm Hg and respiratory rate was 12/min.  Video laryngoscopy examination revealed left vocal cord palsy with no obvious lesion. A whole-body F18 FDG PET–CT scan revealed the presence of 6.6x4.8x6.7 cm lobulated sacullar aneurysm arising from the aortic arch between the origins of the left common carotid and subclavian arteries (figures 1 and 2). The likely mycotic aneurysm caused significant surrounding metabolically active inflammatory changes (figure 3).

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Scarlet Fever

http://otorhinolaryngology-crete.blogspot.com/2017/05/scarlet-fever.html

A 20-year-old man presented to his primary care physician with a 3-day history of swollen tonsils, sore throat, fevers, chills, and rash. The nonpruritic rash had started on his abdomen, spread to his chest and back, and then appeared on his arms, legs, and face. He had no known allergies or exposures to new medications and had no history of similar rash. Examination revealed exudative tonsillitis (Panel A), strawberry tongue, and cervical adenopathy with tenderness. Skin examination revealed diffuse blanching erythema with punctate papules that caused the skin on his chest, abdomen, back, arms, and legs to have a sandpaper-like quality (Panel B shows the left side of his abdomen). His neck and right flank had linear petechial patches. A rapid test for streptococcal pharyngitis was positive. The finding of acute streptococcal pharyngitis along with the diffuse rash led to a diagnosis of scarlet fever. The rash of scarlet fever is a delayed-type hypersensitivity to an exotoxin and therefore occurs in persons who have had a previous exposure to Streptococcus pyogenes. The rash classically manifests with linear petechial confluences that are known as Pastia's lines, which were seen in this patient. The patient was treated with antibiotic agents and had complete resolution of his symptoms within 3 days.

Alyson Brinker, M.D.

Navy Hospital Guam, Yigo, Guam 

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Pediatric nasal surgery prior to puberty is not only safe, but may prevent facial deformity in certain patients.

http://alexandrossfa.blogspot.com/2017/05/pediatric-nasal-surgery-prior-to.html

Pediatric nasal surgery: timing and technique.

από Gary, Celeste C. στο Current Opinion in Otolaryngology & Head and Neck Surgery - Published Ahead-of-Print

Μετάφραση άρθρου

Purpose of review: Timing of pediatric nasal surgery has always been a controversial topic. Concern over disrupting growing parts of the face and causing permanent facial deformity has led to a primarily conservative approach. Many surgeons feel that it is prudent to wait until the patient has completed nasal growth after puberty to pursue nasal surgery. Recent findings: Recently, this attitude has been challenged with evidence that not only is nasal surgery in the pediatric age group not a detriment to facial growth, but failure to correct significant nasal deformity may actually cause dysmorphic facial growth secondary to obligate mouth breathing. Because of this, recent studies have focused on determining safe surgical techniques for pediatric nasal surgery, including inferior turbinate reduction, septoplasty and rhinoplasty. Research focus on this topic has also been expanded to include quality-of-life measures after nasal surgery. Summary: Pediatric nasal surgery prior to puberty is not only safe, but may prevent facial deformity in certain patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

A rounded opacity silhouetting the left heart border and hilum

Pericardial incidentaloma: benign pericardial cyst

από Lin, A. N., Lin, S., Lin, K., Raju, F. στο BMJ Case Reports Last 6 Issues

Μετάφραση άρθρου

Description

A 73-year-old woman with hypertension and atrial fibrillation presented with head and neck injury after mechanical fall. During workup, chest X-ray anteroposterior view (figure 1) revealed a rounded opacity silhouetting the left heart border and hilum. Subsequent contrast-enhanced CT of the chest showed single, 6.4 cm, rounded, well-defined, thin-walled, non-enhanced, low attenuated (–20 and 20 Hounsfield Unit) and homogenous cyst-like structure at the left mediastinum connected to pericardial recesses and not attached to adjacent structures (figure 2A–C). Transthoracic echocardiogram ruled out left ventricular aneurysm, aortic aneurysm, solid tumour and outflow tracts obstruction. Although bronchogenic cyst, oesophageal duplication cyst, thymic tumour and mediastinal lymphoma were considered as possible differentials, radiological features such as CT appearance, homogenous attenuation, unrelated to the underlying structures favoured pericardial cyst. Since patient was asymptomatic, patient and family member were unwilling to undergo surgical removal and pathological confirmation. Follow-up with non-enhanced CT of...

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Transient hemiparaesthesias and dysarthria

Mitral Stenosis

από Oehler, A. C., Sullivan, P. D., Mansoor, A. M. στο BMJ Case Reports Last 6 Issues

Μετάφραση άρθρου

Description

A previously healthy 29-year-old Mexican woman presented to an emergency department with transient hemiparaesthesias and dysarthria. There was no evidence of stroke on cross-sectional imaging of the head, and she was discharged without a clear diagnosis. Two days later, she returned with acute abdominal pain. Abdominal imaging revealed complete occlusion of the right renal artery, prompting emergency embolectomy. Following the procedure, she developed acute haemoptysis, dyspnoea and hypoxaemia. Chest imaging demonstrated evidence of pulmonary venous hypertension. Cardiac auscultation revealed an opening snap followed by a diastolic murmur with presystolic accentuation. These sounds were better appreciated in combination with phonocardiography, a technique supplanted by echocardiography in the 1970s1 that visualised heart sounds (video 1). An echocardiogram confirmed the presence of mitral stenosis (MS), unifying the syndrome of embolic phenomena, haemoptysis and pulmonary hypertension. She underwent successful mitral valve replacement and has since returned to normal...

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Management of Massive Hemoptysis with Oren Friedman

http://sfaki.blogspot.com/2017/05/management-of-massive-hemoptysis-with.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Mismatch repair cancer syndrome (MMRCS) : Multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity.

http://sfaki.blogspot.com/2017/05/mismatch-repair-cancer-syndrome-mmrcs.html

Haematologica. 2010 May; 95(5): 699–701.

doi:  10.3324/haematol.2009.021626

PMCID: PMC2864372

Constitutional mismatch repair-deficiency syndrome

Katharina Wimmer1 and Christian P. Kratz2

1 Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

2 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20852, USA. E-mail: ta.ca.dem-i@remmiw.anirahtak

Katharina Wimmer, PhD, is Associate Professor at the Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck. She is supervising the onco-genetic laboratory for the diagnostics of cancer predisposition syndromes which are also her main research interest. Christian P. Kratz, M.D. is an investigator in the Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics at the National Cancer Institute, National Institutes of Health. His research focuses on individuals with inherited cancer predispositions.

Author information ▼ Copyright and License information ►

See "Constitutional mismatch repair deficiency and childhood leukemia/lymphoma – report on a novel biallelic MSH6 mutation" on page 841.

This article has been cited by other articles in PMC.

The mismatch repair (MMR) machinery contributes to genome integrity and the MLH1, MSH2, MSH6 and PMS2 genes play a crucial role in this process. MMR corrects single base-pair mismatches and small insertion-deletion loops that arise during replication. Moreover, the MMR system is involved in the cellular response to a variety of agents that damage DNA1 and in immunoglobulin class switch recombination.2 Heterozygous germline mutations in MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome (LS), an autosomal dominant cancer syndrome associated with hereditary non-polyposis colorectal cancer (HNPCC), endometrium carcinoma and other malignancies, occurring on average in the fourth and fifth decade of life. Notably, LS associated tumors display somatic loss of the remaining wild type MLH1, MSH2, MSH6 or PMS2 allele and evidence of microsatellite instability (for review see 3).

In contrast to individuals with LS who harbor a heterozygous mutant MMR gene allele, rare cases with biallelic deleterious germline mutations in MMR genes leading to constitutional mismatch repair-deficiency (CMMR-D) have been recognized since 1999.4,5 This cancer syndrome is characterized by a broad spectrum of early-onset malignancies and a phenotype that resembles neurofibromatosis type 1. In this issue of Haematologica, Ripperger and colleagues report on a patient with CMMR-D caused by a novel MSH6 mutation leading to a T-cell lymphoma and colonic adenocarcinoma at six and 13 years of age, respectively. In addition, they review 26 leukemia and/or lymphoma cases reported previously.6

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The clinical presentation and tumor spectrum of CMMR-D

Our knowledge of the CMMR-D syndrome originates primarily from the medical literature; consequently, potential publication bias must be kept in mind as we interpret these reports. Table 1 summarizes the malignancies observed in 89 reported6–11 and 3 unreported cases of CMMR-D. Neoplasms can be divided into four groups: (1) hematologic malignancies (reviewed in 6); (2) brain tumors; (3) LS-associated tumors; and (4) other malignancies. Notably, 31 out of the known 92 CMMR-D patients developed more than one malignancy, and in 19 cases the second or third neoplasm was an LS-associated tumor.

Table 1.

List of malignancies in 92 CMMR-D patients.

In some cases of CMMR-D, areas of skin hypo-pigmentation have been reported.12–15 However, signs reminiscent of neurofibromatosis type 1 (NF1), in particular café-aulait macules (CALMs), are much more common and were observed in the majority of the reported cases (63/92). There are only 2 patients explicitly reported to lack CALMs or other signs of NF1.9,13 Interestingly, several reports stress that CALMs in patients with CMMR-D differ from typical NF1-associated CALMs in that they vary in their degree of pigmentation, have irregular borders, and may display a segmental distribution. Other features of NF1 found in CMMR-D patients include skinfold freckling, Lisch nodules, neurofibromas and tibial pseudarthrosis. Hence, it is not surprising that a number of CMMR-D cases were initially diagnosed as having NF1. It has been speculated that the NF1-like clinical features in CMMR-D result from germline mosaicism arising early during embryonic development. The identification of a truncating NF1 mutation in the blood of one patient16 and data supporting the notion that the NF1 gene is a mutational target of MMR deficiency17 are in line with this assumption. However, extensive mutation analysis in other CMMR-D patients has not confirmed this theory (see 8,12,18 and papers cited therein).

Péron et al.2 have shown in 3 CMMR-D patients that constitutional PMS2 deficiency leads to impaired immunoglobulin class switch recombination characterized by increased serum IgM concomitant with decrease or absence of IgG2, IgG4, and IgA. Of note, one CMMR-D patient initially presented with a primary immunodeficiency,2 and patients with biallelic MSH2 and MSH6 mutations also show IgG2 and/or IgA deficiency 15,19,20. It remains to be seen whether defective IgA and IgG production is a common feature of CMMR-D. Fortunately, severe bacterial infections have not been reported to occur at high frequencies in persons with CMMR-D.

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Genotype-phenotype correlation of CMMR-D

A review of the literature suggests that the clinical features in patients with biallelic germline mutations of MLH1 or MSH2 differ from those with biallelic germline mutations of MSH6 or PMS2 (Table 2). Hematologic malignancies appear to occur more frequently in patients with MLH1 or MSH2 mutations than in patients with mutations of MSH6 or PMS2. In contrast, the latter group appears to have a higher prevalence of brain tumors. Furthermore, tumors tend to develop earlier in MLH1 or MSH2 mutation carriers than in patients with a mutation of MSH6 or PMS2. Patients with biallelic mutations in MSH6 or PMS2 are more likely to survive their first tumors and develop a second malignancy. Overall, the prevalence of LS-associated tumors is higher in patients with biallelic MSH6 or PMS2 mutations than in biallelic MLH1 or MSH2 mutation-positive individuals (Table 2). These factors facilitate the clinical diagnosis of CMMR-D in patients with mutations of MSH6 or PMS2 and may at least partly explain the preponderance of PMS2 mutations in published cases.

Table 2.

Differences in the overall tumor spectrum and age of malignancy onset between carriers of biallelic MLH1/MSH2 and MSH6/PMS2 mutations, respectively.

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Strategies for clinical and subsequent molecular diagnosis of CMMR-D

In view of the wide tumor spectrum that overlaps with Lynch and Turcot syndrome but also includes hematologic malignancies and embryonic tumors such as neuroblastoma, Wilms tumor and rhabdomyosarcoma (Table 1), CMMR-D should be considered in the differential diagnosis in all patients with malignancies (except clearly NF1-associated tumors) who show one or more of the following features: (1) CALMs and/or other signs of NF1 and/or hypo-pigmented skin lesions; (2) consanguineous parents; (3) family history of LS-associated tumors; (4) second malignancy; and (5) sibling with childhood cancer. It is important to note that especially in patients with PMS2 mutations, the family history will often not fulfill the Amsterdam or revised Bethesda criteria for LS.

Typically, confirmation of the diagnosis involves the analysis of microsatellite instability (MSI) and/or immunohistochemistry (IHC), followed by mutation analysis. MSI analysis follows current protocols used for LS-screening; however, this analysis may be unreliable in CMMR-D related brain tumors.7,11,21 IHC is a useful technique employed in patients with CMMR-D associated neoplasms including brain tumors and guides subsequent mutation analysis in the four MMR-genes. In general, a truncating mutation in PMS2 or MSH6 will result in isolated loss of these proteins, whereas a mutation in MLH1 or MSH2 will lead to concurrent loss of MLH1/PMS2 or MSH2/MSH6, respectively, since MLH1 and MSH2 are the obligatory partners in the formation of MLH1/PMS2 and MSH2/MSH6 heterodimers. Notably, in the case of an underlying missense mutation, IHC may show normal results. As CMMR-D patients constitutively lack the expression of one of the MMR genes, IHC detects loss in both neoplastic and non-neoplastic tissues. Conveniently, expression loss of one of the MMR genes can be demonstrated in blood lymphocytes (e.g. by Western blot 2). Similarly, it has been shown that MSI can be determined in normal non-neoplastic tissue of CMMR-D patients by analyzing DNA samples that are diluted to approximately 0–3 genome equivalents per PCR-reaction.22 Nonetheless, standardized procedures for the detection of MMR expression loss and MSI in non-neoplastic tissue from CMMR-D patients have not been developed to date. The diagnosis of CMMR-D should be confirmed by gene-specific mutation analysis. Reliable methods for all four MMR genes including PMS2 are now available.12 Mutation analysis will facilitate identification and surveillance of heterozygous and homozygous individuals in the wider family, and allow for informed decision-making about prenatal or pre-implantation genetic diagnosis.

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Treatment and surveillance of the patient and counseling of relatives

Genetic counseling should be offered to the parents prior to testing of the affected child, and should include information on the potential 25% recurrence risk and on the clinical consequences of a possible heterozygous mutation in both parents. Predictive testing following the established interdisciplinary counseling guidelines should be offered to all family members once a mutation has been identified. Heterozygous family members should be followed according to current LS-guidelines.23

Because of the wide spectrum of malignancies in CMMR-D patients, defining recommendations for surveillance of affected patients remains a challenge. Early diagnosis of CMMR-D and subsequent cancer screening at regular intervals may increase the likelihood of detecting associated cancers, such as colon cancer or brain tumors, at an operable stage. In theory, this screening could include regular exams such as: (1) clinical evaluation; (2) blood tests with full blood count and carcinoembryonic antigen (CEA); (3) magnetic resonance imaging of the brain; (4) endoscopic examination of the gastrointestinal tract; and (5) endometrial sampling and transvaginal ultrasound for endometrial and ovarian cancer. However, these recommendations rest only on clinical judgment and do not represent a standard of care. To date there is no available evidence to support any of these recommendations or to provide guidance on the optimal frequency of such tests. Likewise, there is currently no information available regarding the optimal treatment of CMMR-D patients. Several reports stress that careful attention should be given to the possibly increased cyto-toxicity and reduced efficacy of chemotherapeutic agents due to constitutionally impaired mutation repair, and the high risk of a second malignancy 6,8,14,15.

Reports such as the article by Ripperger and colleagues are valuable in increasing awareness and knowledge of the syndrome in the clinical community. Nevertheless, systematic studies are needed in order to better define the phenotype of MMR-D. Data related to cancer screening, treatment and outcome should be collected and evaluated systematically to provide a basis for recommendations on how to manage patients with CMMR-D.

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Footnotes

( Related Original Article on page 841)

We thank Drs. Anne Durandy and Johannes Zschocke for their helpful comments on the manuscript. Dr. Kratz's work was supported by the Intramural Research Program of the US National Cancer Institute.

No potential conflict of interest relevant to this article was reported.

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6. Ripperger T, Beger C, Rahner N, Sykora KW, Bockmeyer CL, Lehmann U, et al. Constitutional mismatch repair deficiency and childhood leukemia/lymphoma - report on a novel biallelic MSH6 mutation. Haematologica. 2009 Dec 16; [Epub ahead of print] [PMC free article] [PubMed]

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9. Sjursen W, Bjornevoll I, Engebretsen LF, Fjelland K, Halvorsen T, Myrvold HE. A homozygote splice site PMS2 mutation as cause of Turcot syndrome gives rise to two different abnormal transcripts. Fam Cancer. 2009;8(3):179–86. [PubMed]

10. Toledano H, Goldberg Y, Kedar-Barnes I, Baris H, Porat RM, Shochat C, et al. Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. Fam Cancer. 2009;8(3):187–94. [PubMed]

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