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Home , Bosentan, Carisoprodol, Clindamycin, Colesevelam, Exemestane, Felbamate

3/2/2015

FacultyFaculty Pharmacology Update: Interactions of Oral Nancy Bishop, RPh Contraceptives and Assistant State Pharmacy Director Medications to Drugs and Alabama Department of Public Health Herbal Remedies Satellite Conference and Live Webcast Wednesday, March 4, 2015 8:30 – 10:30 am Central Time

Produced by the Alabama Department of Public Health Video Communications and Distance Learning Division

Classifications of Interactions Classifications of Interactions • Level 1: Severe - Avoid – Consider alteration in therapy and – Using these medications together monitor patients is contraindicated • Level 3: Moderate – Rare exceptions may exist – Using these medications together • Level 2: Major may result in unintended clinical effects – Using these medications together may be contraindicated for a select – Alterations in therapy may group of patients be required

Classifications of Interactions – Monitor patients • Level 4: Minor Drug-Drug and Drug-Herbal – Using these medications together Interactions of usually does not result in clinically Oral Contraceptives significant interactions

1 3/2/2015

Level 1 Interactions with OC Protease Inhibitors • Amprenavir (Agenerase): • OC’s decrease the HIV Protease Inhibitor concentrations of Amprenavir • Fosamprenavir (Lexiva): and Fosamprenavir HIV Protease Inhibitor • Increase of OC’s: • Inhibitors: , Lopinavir, Ritonavir, Hormonally-responsive Nelfinavir, Saquinavir, Tipramavir • (Tracleer): Pulmonary arterial • Decrease metabolism of OC’s: • Metopirone (): Atazanavir and HPA Diagnosis

Protease Inhibitors Aromatase Inhibitors • Report breakthrough bleeding and • could interfere with action other adverse effects to physician and of aromatase inhibitors , decreasing use barrier method of contraception circulating levels and inhibiting growth of hormonally- responsive cancers • Estrogen therapy is not recommended due to opposing pharmacologic actions

Aromatase Inhibitors Bosentan (Tracleer) • Includes: • Contraindicated – (cytadren) • Indicated for treatment of pulmonary arterial hypertension – (Arimidex) • Significant inducer of CYP3A – (Aromasin) hepatic – (Femara) • Decrease in norethindrone serum concentrations as high as 56% and – (Teslac) ethinyl as high as 66% • Teratogenic and contraindicated during

2 3/2/2015

Metopirone (Metyrapone) Question #1 • Estrogen therapy can yield a • True or False sub - therapeutic response – A patient taking an OC and a • Indicated for Hypothalmic - pituitary - protease inhibitor should always adrenal (HPA) suppression diagnosis use a barrier method of • Available only for compassionate use contraception, regardless of the interaction level • Discontinue estrogens prior to and during metyrapone administration

Answer #1Answer #1 Level 2 Interactions with OC • True • HIV Protease Inhibitors: – The most common indication for – Atazanavir Protease Inhibitors is HIV – Indinavir – Lopinavir, Ritonavir – Nelfinavir – Ritonavir – Saquinavir – Tipranavir

Level 2 Interactions with OC Level 2 Interactions with OC • Anti - seizure medications: • – – Rifabutin – – Rifampin – – RfRefapen tine – • : – – – –

3 3/2/2015

Level 2 Interactions with OC Level 2 Interactions with OC • Prophylaxis – : Muscle – – : Blood thinner – – St. John’s Wort • Other – TbTobacco – : – Charcoal: overdose, poisoning – : Narcolepsy

Test Question #2 Answer #2Answer #2 • True or False: • False – A medication listed as a level 2 – Should consider alternative interaction should never be given therapies if possible to a patient receiving oral – If not, closely monitor patients contraceptives

CYP3A4 Inducers CYP3A4 Inducers • Estrogens metabolized by CYP3A4, – Patients at higher risk of therefore susceptible to interactions deficiency with hepatic inducing drugs – Greater risk of neural tube defects – stimulate CYP3A4 when failure occurs thereby causing OC failure – Low - dose estrogen regimens at greater risk (ethinyl estradiol < 50 mcg / day)

4 3/2/2015

Anti - Seizure Medications Anti - Seizure Medications CYP3A4 Inducers CYP3A4 Inducers • May decrease level of contraceptive • No adverse effect if dose is and efficacy: 50 - 200 mg / day – Carbamazepine (Tegretol) – Phenytoin (Dilantin) – Oxcarbazepine (Trileptal) – Fosphenytoin (Cerebyx) – Felbamate (Felbatol) – Topiramate (Topamax): May decrease levels of contraceptive and efficacy if dose is over 200 mg / day

Tuberculosis treatments Tuberculosis treatments CYP3A4 Inducers CYP3A4 Inducers • May decrease level of contraceptive • 70% of women taking estrogen- and efficacy: containing OC and rifampin – Rifampin (Rifadin): experience menstrual abnormalities and 6% • Increases elimination of become pregnant estrogens and progestins – Rifabutin (Mycobutin) • Increases estrogenic protein binding activity – Rifapentine (Priftin)

Anti - Fungal Medications • Fluconazole (Diflucan): Prophylaxis Medications – Clinical significance is unknown • Tamoxifen (Nolvadex): – Variations in increase and – Contraindicated in most, but decrease of hormonal not all, patients concentrations – Oral contraceptives may • Griseofulvin (Fulvicin): aggravate conditions being – CYP3A4 Inducer treated by tamoxifen – May decrease levels of contraceptive and efficacy

5 3/2/2015

Breast Cancer Warfarin (Coumadin) Prophylaxis Medications • Generally avoid OC’s in patients • Raloxifene (Evista): taking Warfarin due to Thromboembolism risks – Blocks estrogen receptors • Weigh risks versus benefits – Illogical to give with estrogen • OC’s can alter INR

Warfarin (Coumadin) Tizanidine (Zanaflex) • OC’s products containing > / = 50 • May increase tizanidine levels mcg Ethinyl Estradiol are associated • Tizanidine clearance in with the greatest risk of decreased 50% Thromboembolic complications • Risk of , , • Addition of progestins may increase psychomotor impairment and other Thromboembolic risks adverse effects

OtherOther OtherOther • Modafinil (Provigil): • Bexarotene (Targretin): – Indicated for narcolepsy – CYP3A4 Inducer – CYP3A4 Inducer - May decrease – Indicated for T- cell lymphoma levels of contraceptive and efficacy – May decrease levels of – May cause failure of OC’s and contraceptive and efficacy hormonal containing implants or devices

6 3/2/2015

OtherOther OtherOther • : • Charcoal: – Increase risk of – Possible absorption issue with thromboembolic disease oral contraceptives – Increased risk for patients 35 – Should take 3 hours after but at years or older or those who least 12 hours before oral smoke 15 or more cigarettes contraceptive per day

OtherOther Level 3 Interactions with OC • St. John’s Wort: • – CYP3A4 inducer • – Loss of contraceptive efficacy • • : Fosaprepitant • • •

Level 3 Interactions with OC Level 3 Interactions with OC • Cyclosporine • • • Mycophenolate • • • Doxercalciferol • Nitrofurantoin • Echinacea • V • • • • Somatropin, rh-GH

7 3/2/2015

Level 3 Interactions with OC Anti - Infectives • Soy Isoflavones • Disruption of normal GI flora may decrease effectiveness of estrogen- • Sulfonamides containing OC’s • • Includes: amoxicillin, ampicillin, • Theophylline, chloramphenicol, clindamycin, lincomycin, neomycin, nitrofurantoin, penicillin V, sulfonamides,

Anti - Infectives Question #3 • anti - infectives may • True or False increase estrogen metabolism – Patients should always be – Dirithromycin, erythromycin, counseled to use an alternative clarithromycin means of contraception while • Incidence of the interaction between taking anti - infectives and OC’s is unpredictable and those most at risk for OC failure cannot be identified

Answer #3Answer #3 Lamotrigine (Lamictal) • True • Indicated for and – At least for me • It is a liability issue • May decrease level resulting in contraceptive failure • Estradiol and may decrease lamotrigine levels resulting in a need for increased dosing

8 3/2/2015

Lamotrigine (Lamictal) Theophylline (Theo-24) • Side effects • Indicated for and – Ex: , , and bronchospasm may occur during / off week • May increase theophylline levels • Progestin - only products are not • Risk of theophylline known to change lamotrigine levels • CYP3A4 and CYP1A2 substrate • Inhibits hepatic metabolism

Cyclosporine Selegiline (Eldepryl) • Indicated for organ transplant • Indicated for Parkinson disease rejection prophylaxis, rheumatoid • May increase selegiline total arthritis and concentrations as much as 20 - fold • CYP3A4 substrate with moderate due most likely to decreased CYP3A4 inhibitor characteristics metabolism of selegiline • May increase cyclosporine levels • May be necessary to reduce dose with risk of toxicity of selegiline • Increased risk of

Ambrisentan (Letairis) Aprepitant (Emend) • Indicated for pulmonary • Aprepitant: arterial hypertension – Indicated for prevention of • Restricted distribution in the chemo-related and – Fosaprepitant (Emend Injection) • CYP3A4 substrate – Minor CYP3A4 inducer and moderate CYP3A4 inhibitor

9 3/2/2015

OtherOther OtherOther • Mycophenolate Mofetil (CellCept): • Somatropin, rh - GH (): Indicated for prevention of organ transplant rejection – Indicated for growth hormone deficiency – One study showed decreased level of – Induced hepatic metabolism may • Dantrolene: Indicated for spasticity decrease hormonal contraceptive – Increased risk of levels resulting in failure • Doxercalciferol: Indicated for – May accelerate epiphysial maturation hyperparathyroidism

Herbs and OTC’s Level 4 Interactions with OC • Echinacea: • Antidiabetic Agents – Inhibits intestinal CYP3A4 but • Antihypertensive Agents induces hepatic CYP3A4 – Clinical significance unknown • Ascorbic Acid, C • Soy Isoflavones: • Atorvas ta tin – Similar chemical structure to • synthetic and natural estrogens • – Clinical significance unknown • salts – Use with caution

Level 4 Interactions with OC Level 4 Interactions with OC • • Mineral Oil • • • Delavirdine • Neuromuscular Blockers • Food • • Grapefruit juice • • Green • • • Tricyclic • • Urosodeoxycholic Acid, Urosdiol

10 3/2/2015

Anti - Diabetic Medications Anti - Diabetic Medications • OC’s decrease hypoglycemic effect • (Actos) may decrease by impairing tolerance OC effectiveness by increasing • More common in patients receiving metabolism of estrogens > 50 mcg ethinyl estradiol per day • (Byetta) may reduce rate • Closely monitor patients when OC and/or extent of absorption of OC’s therapy is initiated and when – Take OC at least one hour prior to discontinued exenatide injection

Anti - Hypertensives StatinsStatins • Estrogen can induce fluid retention • (Lipitor) and and may increase in Rosuvastatin (Crestor) some patients • Indicated for • Monitor patients to confirm target • May increase contraceptive blood pressure is achieved hormonal levels, mostly likely, due to competition for CYP3A4 substrate • Clinical significance unknown

Benzodiazepines Benzodiazepines • Ethinyl estradiol may increase levels • Conversely, ethinyl estradiol may of some benzodiazepines, including: enhance metabolism of Lorazepain – (Librium) (Ativan), (Serax), and (Restoril) – (Tranxene) • Observe patients for evidence of – (Klonopin) increased or decreased response – (Valium) – (Halcion), and others

11 3/2/2015

Corticosteroids Thyroid Hormones • May potentiate the anti - inflammatory • Estrogens cause abnormal thyroid effects of hydrocortisone function test results • Estrogens increase serum thyroxine • May delay clearance of prednisolone binding globulin • Monitor patients receiving • PtitPatients may h ave a d ecreased hydrocortisone and prednisolone clinical response due to decreased free thyroxine levels • No evidence of interaction with , • Thyroid hormone dose adjustments may be necessary and

Tricyclic Antidepressants OtherOther • Ethinyl estradiol may decrease • Neuromuscular Blockers: Prolonged neuromuscular blockade may occur metabolism of tricyclic antidepressants, thereby, increasing • Cimetidine (Tagamet): Reduces hepatic clearance of estradiol - Monitor for serum concentrations estrogen related side effects • Side effects of may • Ursodiol (Actigall): OC may increase be increased hepatic secretion and increase cholesterol gallstone • More significant interaction probable formation, thereby, counteracting the with ethinyl estradiol doses of 50 mcg effectiveness of ursodiol or greater per day

OtherOther OtherOther • Nefazodone (Serzone): • Delavirdine (Rescriptor): – Indicated for – Indicated for HIV – Inhibits CYP3A4 isoenzyme – Serum concentration of ethinyl – May increase estrogen - related estradiol may be increased side effects – Clinical significance is unknown – Clinical significance unknown

12 3/2/2015

Question #4 Answer #4Answer #4 • True or False • True – Patients should always be asked – Most people do not consider what prescription medications, and “natural” products as vitamins, herbals and part of their medication regimen over - the - counter medications but these can affect how their they are taking medications work

Other CYP3A4 Inhibitors Other CYP3A4 Inhibitors • Grapefruit juice: • (ascorbic acid): – Decreases estradiol metabolism – May increase ethinyl estradiol – Estrogen levels may increase up up to 50% to 30% – May see increase in estrogen – Clinical significance is unknown related side effects

OtherOther OtherOther • Calcium salts: • Mineral Oil – Estrogen increase calcium – Simultaneous administration may absorption which can be beneficial decrease absorption of estrogens • Caffeine: – Separate doses by giving – Includes , green tea , other , est1hbf2htrogens 1 hour before or 2 hours colas, guarana, and after mineral oil – Serum concentrations of caffeine may be increased by ethinyl estradiol – Monitor for caffeine - related side effects

13 3/2/2015

Gabapentin (Neurontin) • Indicated for treatment of partial seizures Drug-Drug and Drug-Herbal • Has high Interactions of Seizure • Not metabolized by the Medications • Has no protein binding • No enzyme induction - related drug interactions

Gabapentin (Neurontin) Gabapentin (Neurontin) • Does not alter serum concentration • Level 2 interactions: of other anticonvulsants and other – Antacids (aluminum hydroxide and anticonvulsants do not alter serum hydroxide): concentration of Gabapentin • When taken together reduces • No level 1 interactions bioavailability by 20% • Take gabapentin at least 2 hours after antacid

Gabapentin (Neurontin) Gabapentin (Neurontin) – : – Sevelamer (Renagel): • With • Potential for reduces drug (Horizant Extended Release), absorption Gabapentin is released faster • All gabapentin there is a • Separate dose of Gabapentin at increased risk of drowsiness least 1 hour before or 3 hours and dizziness after Sevelamer • Patients should avoid consumption

14 3/2/2015

Gabapentin (Neurontin) Gabapentin (Neurontin) – Level 3 interactions: • : May decrease • : May increase concentration of Hydrocodone Gabapentin serum concentration and increase concentration of –Monitor patient for signs of Gabapentin CNS depress an d a djust –Is Gabapentin dose dependent, dose of each as necessary with lower doses having • : Increases amount of less effect Gabapentin absorbed by 12 - 15% –Clinical significance unknown –Monitor patients and adjust doses of each

Gabapentin (Neurontin) Gabapentin (Neurontin) • Colesevelam: For safety, give Level 3 Interactions gabapentin at least 4 hours • Medications that may enhance before colesevelam CNS depression (e.g. drowsiness and dizziness): –, and –:

Gabapentin (Neurontin) Gabapentin (Neurontin) Level 3 Interactions Level 3 Interactions • , , • (Soma), , Molindone, (Robaxin) , Quetiapine, –Phenothizines and Tricyclic anti - : –Antiparkinson’s Disease: • Amoxapine, Maprotiline, • Entacapone, Pramipexole, , Nefazodone, , Tolcapone

15 3/2/2015

Gabapentin (Neurontin) Gabapentin (Neurontin) Level 3 Interactions • Level 4 interactions: – (Ultram) – Cimetidine (Tagamet) –Sedating H1 blockers • Gabapentin clearance reduced but not clinically significant – antitussive or – (Inderal) expectorant combinations; and • Higher doses of propranolol may induce dystonia combinations • Monitor patient and lower propranolol dose if necessary

Lamotrigine (Lamictal) Lamotrigine (Lamictal) • Indicated for partial seizures and • Level 2 interactions: tonic - clonic seizures – Acetaminophen (): • Off-label use in absence seizures • Doses of 900 mg tid or more • Metabolized via accelerates lamotrigine • Caution when adding and clearance by 15% discontinuing medications once – Atazanavir (Reyataz): seizure control has been achieved • Increases metabolism of • No level 1 interactions lamotrigine

Lamotrigine (Lamictal) Lamotrigine (Lamictal) • Adjust dose with addition or – Clozapine: discontinuation of Atazanavir • Can increase Clozapine – Cabamazepine: concentration by 3 fold • May stimulate metabolism of • Lowering of seizure threshold Lamotrigine, decreasing level of dose dependent Lamotrigine as much as 40% – Desmopressin (DDAVP): • Increase risk of water intoxication with

16 3/2/2015

Lamotrigine (Lamictal) Lamotrigine (Lamictal) • Level 2 interactions: – Rifampin: – Methsuximide (Celontin): • Increased Lamotrigine clearance resulting in decrease • Reduces serum concentrations anticonvulant efficacy of Lamotrigine by up to 70% – SlSevelamer (RlRenagel): • Caution when discontinuing • Potential for reduces absorption Methsuximide • Separate Lamotrigine doses by at least one hour before or three hours after Sevelamer

Lamotrigine (Lamictal) Lamotrigine (Lamictal) • Level 2 interactions: • Increased side effects during placebo / off week are possible – Oral and non - oral combination • Clinical significance of clearance contraceptives: changes is unknown • May require close clinical • Changes li mit ed t o th e pill f ree monitoring week are not recommended • Estrogen may increase • May consider progestin - only Lamotrigine clearance contraceptives or extended cycle combined hormonal contraceptive

Lamotrigine (Lamictal) Lamotrigine (Lamictal) • Level 3 Interactions: • May require lamotrigine dose adjustment – Phenytoin and Fosphenytoin: – (, • Induces hepatic enzymes mephobarbital, ): • When a dded t o regi ment , can • Induces hepatic enzymes reduce steady state concentration of Lamatrigine • When added to regiment, can up to 50% reduce steady state concentration of lamatrigine up to 40%

17 3/2/2015

Lamotrigine (Lamictal) Lamotrigine (Lamictal) • May require lamotrigine dose • Level 3 Interactions: adjustment – Valproic acid: – Oxcarbazepine: • More than doubles the • Increases clearance of elimination half - life and lamotrigine up to 29% steady - state concentration • Monitor for , dizziness, of Lamatrigine nausea and • Adjust dose if Valproic acid is discontinued

Lamotrigine (Lamictal) Lamotrigine (Lamictal) – Topiramate: • Level 3 Interactions: • May decrease Topiramate serum – Ritonavir: concentration • Increases hepatic metabolism • Clinical significance is unknown resulting in decreased – Buproprion: Lamatrigine concentrations • A drug - disease interaction • Dose increase of Lamotrigine • Should not be used in patients may be necessary with a pre - existing seizure disorder

Lamotrigine (Lamictal) Lamotrigine (Lamictal) – inhibitors – Colesevelam: (, 5-FU, , • Change in concentration can be , ): clinically significant • All inhibit dihydrofolate • Give Lamotrigine at least 4 hours reductase before Colesevelam • Use with caution

18 3/2/2015

Topiramate (Topamax) Topiramate (Topamax) • Indicated for partial seizures, tonic - • Alcohol withdrawal or excessive use clonic seizures and Lennox - Gastaut may lower seizure threshold seizures • Avoid doses over 200 mg / day if • Metabolized minimally by the liver using hormonal contraceptives • Is a minor CUP3A4 inducer and a weak CYP2C19 inhibitor • Avoid alcohol consumption

Topiramate (Topamax) Topiramate (Topamax) • Level 1 Interaction: • Level 2 Interactions: – Probenecid: – : • Significant increase in renal • Topiramate can cause metabolic clearance of Topiramate acidosis and may increase serum • May lower Topiramate levels concentration of metformin • Shown in animals only; no • Best to avoid taking both but if human trials necessary, closely monitor patients

Topiramate (Topamax) Topiramate (Topamax) – Oral and non - oral contraceptives: • Level 2 Interactions: • Increase clearance of Ethinyl – Ethanol: Estradiol • Alters pattern of Topiramate • More risk at doses over release from extended - release 200 mg / day capsules • Do not consume alcohol within 6 hours (before and after) taking Topiramate

19 3/2/2015

Topiramate (Topamax) Topiramate (Topamax) – Dolutegravir: • Level 2 Interactions: • Decrease Dolutegravir levels – (HCTZ): – Tramadol: • May potentiate - wasting • May cause CNS depress ion an d • Clinical significance is unknown cognitive and / or • May require reduction in neuropsychiatric reactions Topiramate dose when HCTZ is added and dose increase when • Decrease seizure threshold HCTZ is discontinued

Topiramate (Topamax) Topiramate (Topamax) – inhibitors: • Level 2 Interactions: • Increased risk of renal stone – : formation • May cause subtherapeutic levels • Increased risk for heat - related of Telithromycin disorders, e.g. heat • May result in increase serum • Increased risk of bleeding concentration of Topiramate with • Includes , increase in adverse effects Methazolamide, Dichlorphenamide

Topiramate (Topamax) Topiramate (Topamax) – Sevelamer: – : • Potential for reduced drug • May decrease Linagliptin to absorption with potential for loss subtherapeutic levels of efficacy • Alternative to Linagliptin is • Separate dose of Topiramate at recommended least 1 hour before or 3 hours after Sevelamer

20 3/2/2015

Topiramate (Topamax) Topiramate (Topamax) • Level 2 Interactions: Level 3 Interactions – Valproic acid: • • May result in decrease in • Valproic acid and Topiramate • Antimuscarinics serum concenttitrations • • Associated with • Barbiturates • • Associated with hypothermia • Carbamazepine • May increase risk of bleeding

Topiramate (Topamax) Topiramate (Topamax) Level 3 Interactions Level 3 Interactions • Colesevelam • • Dasabuvir • Ezagabibe • Ombitasvir • Felbamate • Paritaprevir • Fosphenytoin • Ritonavir • Lamotrigine • • • Estrogens •

Topiramate (Topamax) Topiramate (Topamax) Level 3 Interactions Level 3 Interactions • Loop • Platelet Inhibitors • Metformin • • NSAIDS • Risperidone • Opiate • • Oxcarbazepine • Salicylates • Phenytoin • SSRIs • Pioglitazone • diuretics

21 3/2/2015

Topiramate (Topamax) Topiramate (Topamax) Level 3 Interactions • Level 4 Interactions: • – (Vfend) • • An antifungal • MltiiiMay result in an increase in Voriconazole concentrations • Clinical significance is unknown

Pregabalin (Lyrica) Pregabalin (Lyrica) • Indicated for partial seizures • Level 2 Interactions: • No drug interactions of clinical – Angiotensin - converting enzyme significance due to inhibition of the inhibitors (ACE Inhibitors): CYPP450 enzymes have been • May cause life - threatening reported with respiratory • No level 1 or level 4 interactions compromise • Raw ginkgo seeds: May decrease efficacy

Pregabalin (Lyrica) Pregabalin (Lyrica) – Examples of ACE inhibitors: • Level 3 Interactions: • Accupril – Thiazolidinediones (pioglitazone, • , ): • ElEnalapr il • Higher rates of peripheral and weight gain • • May exacerbate or lead to

22 3/2/2015

Pregabalin (Lyrica) Pregabalin (Lyrica) Level 3 Interactions: Level 3 Interactions: •• May potentiate CNS effects such as –– AnxiolyticsAnxiolytics,, Sedatives and and cognitive and gross HypnoticsHypnotics motor function: –– Barbiturates –– OpioidsOpioids –– –– EthanolEthanol –– General –– –– –– Sedating H1-H1-blockers –– THC,

Pregabalin (Lyrica) Divalproex Level 3 Interactions: (Depakote) and Valproic –– NabiloneNabilone Acid (Depakene) –– •• Indicated for absence, myoclonic,myoclonic, partial and tonic - clonic seizures –– •• No Level 1 interactions –– Tolcapone •• Metabolized by hepatic CYP450 –– Tricyclic Antidepressants microsomal enzymes, CYP2C19 and CYP2C9, and UGT –– Carbinoxamine –– Therefore, interactions can –– CarbidopaCarbidopa,, LevodopaLevodopa,, Entacapone be significant

Divalproex Sodium Divalproex Sodium (Depakote) and Valproic (Depakote) and Valproic Acid (Depakene) Acid (Depakene) •• Ginkgo: May decrease •• Carbinoxaine and :Doxylamine: anticonvulsant efficacy Increased risk of CNS depression, •• Omacetaxine mepesuccinate and psychiidhomotor impairment and tositumomabtositumomab:: May increase risk adverse effects of bleeding

23 3/2/2015

Divalproex Sodium Divalproex Sodium (Depakote) and Valproic (Depakote) and Valproic Acid (Depakene) Acid (Depakene) • Level 2 Interactions: – Carbamazepine: – : • May increase clearance and dtdecrease serum concentratition • Includes , , of valproic acid , and • May decrease metabolism of • May decrease valproic acid to carbamazepine’s active metabolite causing vomiting and subtherapeutic levels tiredness, especially in children

Divalproex Sodium Divalproex Sodium (Depakote) and Valproic (Depakote) and Valproic Acid (Depakene) Acid (Depakene) • Level 2 Interactions: – Isoniazide (INH): – Rifampin: • May inhibit valproic acid • May increase clearance of hepatic metabolism valproic acid and rifampin • Increases valproic acid • Adjust valproic dose as concentrations and necessary hepatotoxicity

Divalproex Sodium Divalproex Sodium (Depakote) and Valproic (Depakote) and Valproic Acid (Depakene) Acid (Depakene) – Topiramate: • Haloperidol • May cause hyperammonemia. • Loxapine • May cause hypothermia • Maprotiline – Interactions that may cause • Monoamine oxidase inhibitors additive CNS depression and can (MAOIs) lower seizure threshold:

24 3/2/2015

Divalproex Sodium Divalproex Sodium (Depakote) and Valproic (Depakote) and Valproic Acid (Depakene) Acid (Depakene) • Level 2 Interactions: – : – Dasabuvir, Ombitasvir, • May increase systemic exposure Paritaprevir, Ritonavir, Tipranavir, of sodium oxybate Lopinavir: • May impair attention and • May decrease valproic acid tests concentration and efficacy

Divalproex Sodium Divalproex Sodium (Depakote) and Valproic (Depakote) and Valproic Acid (Depakene) Acid (Depakene) • Reduce sodium oxybate dose by – Cholestyramine: at least 20% when valproic acid • May decrease bioavailability of treatmenttt tiiititd is initiated valproic acid • Closely monitor patient and • Separate valproic acid dose at make further dose adjustments if least 2 hours before or 6 hours necessary after cholestyramine

Divalproex Sodium Divalproex Sodium (Depakote) and Valproic (Depakote) and Valproic Acid (Depakene) Acid (Depakene) – Sevelamer: Level 3 Interactions • Barbiturates • Potential for reduced absorption • BiBupropion • Separate valproic acid dose by at • Clonazepam least 1 hour before or 3 hours • Clozapine after sevelamer • Colesevelam • Ethanol

25 3/2/2015

Divalproex Sodium Divalproex Sodium (Depakote) and Valproic (Depakote) and Valproic Acid (Depakene) Acid (Depakene) Level 3 Interactions Level 3 Interactions • • Methsuximide • Etho to in • NSAIDs • Felbamate • Paliperidone • Fosphenytoin • Phenothiazines • Lamotrigine • Phenytoin • • Salicylates

Divalproex Sodium Divalproex Sodium (Depakote) and Valproic (Depakote) and Valproic Acid (Depakene) Acid (Depakene) Level 3 Interactions Level 4 Interactions • • Antacids • TiTricyc licantidepressant s • Asenapine • Voriconazole • Diazepam • Warfarin • • • Oxcarbazepine

Divalproex Sodium Levetiracetam (Keppra) (Depakote) and Valproic • Adjunctive therapy in treatment of Acid (Depakene) partial, myoclonic and generalized Level 4 Interactions tonic - clonic seizures • Risperidone • Minimal interactions with other antiepppileptic medications • • No drug interactions with commonly • Zidovudine prescribed medications • Not an inhibitor nor has high affinity for hepatic P450 enzymes • No Level 1 interactions

26 3/2/2015

Levetiracetam (Keppra) Levetiracetam (Keppra) • Level 2 Interactions: • Level 4 Interactions: – Sevelamer: – Probencid: • Potential for reduced absorption • The major metabolite of • StSeparate ltitlevetiracetam dbdose by levetiracetam was at least 1 hour before or 3 hours approximately doubled after sevelamer • Renal clearance of metabolite may decrease up to 60% • Clinical significance unknown

Levetiracetam (Keppra) Levetiracetam (Keppra) • Level 3 Interactions: – Colesevelam: – Ethanol: • May alter levetiracetam serum • May lead to loss of seizure concentrations control • Give levetiracetam dose at least • May increase drowsiness and 4 hours before colesevelam dizziness

Levetiracetam (Keppra) Phenytoin (Dilantin) – Carbamazepine: • Indicated for tonic – clonic and partial seizures with complex • Pharmacodynamic interaction symptomatology • Carbamaxepine toxicity • Mechanisms of drug interactions may symptoms of ataxia, be complex and unsteady gait reported with • Induces of hepatic P450 enzymes levetiracetam doses equal to or (CYP3A4, CYP2C9, CYP2C19) greater than 500 mg twice a day • Interactions also influenced by patient’s age, presence of and cigarette smoking history

27 3/2/2015

Phenytoin (Dilantin) Phenytoin (Dilantin) Level 1 Interactions Level 1 Interactions • , • • Dasabuvir, Ombitasvir, Paritaprevir, • Ritonavir • Telaprevir • Delavirdine • Etravirine • Ibrutinib •

Phenytoin (Dilantin) Phenytoin (Dilantin) • Over 70 drugs listed as having the – Ethanol potential for a level 2 interaction – Fluconazole • Includes: – St. John’s Wort – Oral and non - oral contraceptives – Vinca alkal oid s – Rifampin – – Protease inhibitors

Phenytoin (Dilantin) Phenytoin (Dilantin) • Over 90 drugs listed as having the – Estrogens potential for a level 3 interaction – • Includes: – Sulfonamides – Antacids – TiTopirama te – PPIs – Trimethoprim – – Valproic acid – –

28 3/2/2015

Phenytoin (Dilantin) Phenytoin (Dilantin) • Over 30 drugs listed as having the – Folic acid potential for a level 4 interaction – Green tea • Includes: – Guarana – Acetaminophen – Flu vacci ne – Acyclovir – Aspirin – Antidiabetic medications – Caffeine

Contact Information

Nancy Bishop, RPh Assistant State Pharmacy Director Alabama Department of Public Health

(334) 206-3014

[email protected]

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