Pan-Ceftriaxone

Pan-Ceftriaxone may be available in the countries listed below.

Ingredient matches for Pan-Ceftriaxone

Ceftriaxone

Ceftriaxone is reported as an ingredient of Pan-Ceftriaxone in the following countries:

• Israel

International Drug Name Search

Cosaar

Cosaar may be available in the countries listed below.

Ingredient matches for Cosaar

Losartan

Losartan potassium salt (a derivative of Losartan) is reported as an ingredient of Cosaar in the following countries:

• Austria


• Switzerland

International Drug Name Search

Abamitel PLUS

Abamitel PLUS may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Abamitel PLUS

Abamectin

Abamectin is reported as an ingredient of Abamitel PLUS in the following countries:

• Poland

Praziquantel

Praziquantel is reported as an ingredient of Abamitel PLUS in the following countries:

• Poland

International Drug Name Search

Atova

Atova may be available in the countries listed below.

Ingredient matches for Atova

Atorvastatin

Atorvastatin calcium (a derivative of Atorvastatin) is reported as an ingredient of Atova in the following countries:

• Bangladesh


• Myanmar

International Drug Name Search

Ultrum

Ultrum may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Ultrum

Bioallethrin

Bioallethrin is reported as an ingredient of Ultrum in the following countries:

• South Africa

Permethrin

Permethrin is reported as an ingredient of Ultrum in the following countries:

• South Africa

Piperonyl Butoxide

Piperonyl Butoxide is reported as an ingredient of Ultrum in the following countries:

• South Africa

Pyriproxyfen

Pyriproxyfen is reported as an ingredient of Ultrum in the following countries:

• South Africa

International Drug Name Search

Solunac

Solunac may be available in the countries listed below.

Ingredient matches for Solunac

Diclofenac

Diclofenac is reported as an ingredient of Solunac in the following countries:

• India

International Drug Name Search

Aseptochrome

Aseptochrome may be available in the countries listed below.

Ingredient matches for Aseptochrome

Merbromin

Merbromin is reported as an ingredient of Aseptochrome in the following countries:

• Luxembourg

International Drug Name Search

Riazem

Riazem may be available in the countries listed below.

Ingredient matches for Riazem

Diltiazem

Diltiazem hydrochloride (a derivative of Diltiazem) is reported as an ingredient of Riazem in the following countries:

• Oman

International Drug Name Search

Naprobene

Naprobene may be available in the countries listed below.

Ingredient matches for Naprobene

Naproxen

Naproxen is reported as an ingredient of Naprobene in the following countries:

• Austria

International Drug Name Search

Oxyterracyna

Oxyterracyna may be available in the countries listed below.

Ingredient matches for Oxyterracyna

Oxytetracycline

Oxytetracycline hydrochloride (a derivative of Oxytetracycline) is reported as an ingredient of Oxyterracyna in the following countries:

• Poland

International Drug Name Search

N-Piracetam

N-Piracetam may be available in the countries listed below.

Ingredient matches for N-Piracetam

Piracetam

Piracetam is reported as an ingredient of N-Piracetam in the following countries:

• Romania

International Drug Name Search

Dipentum

In some countries, this medicine may only be approved for veterinary use.

In the US, Dipentum (olsalazine systemic) is a member of the drug class 5-aminosalicylates and is used to treat Ankylosing Spondylitis, Ulcerative Colitis, Ulcerative Colitis - Active and Ulcerative Colitis - Maintenance.

US matches:

• Dipentum

UK matches:

• Dipentum Capsules (SPC)
• Dipentum Capsules 250 mg, Dipentum Tablets 500 mg (SPC)
• Dipentum Tablets 500mg (Pharmacia Limited) (SPC)

Ingredient matches for Dipentum

Olsalazine

Olsalazine is reported as an ingredient of Dipentum in the following countries:

• New Zealand

Olsalazine disodium salt (a derivative of Olsalazine) is reported as an ingredient of Dipentum in the following countries:

• Australia


• Austria


• Canada


• Chile


• Denmark


• Finland


• France


• Germany


• Hong Kong


• Iceland


• Ireland


• Israel


• Latvia


• Netherlands


• Norway


• Oman


• South Africa


• Sweden


• Switzerland


• United Kingdom


• United States

International Drug Name Search

Glossary

SPC	Summary of Product Characteristics (UK)

Click for further information on drug naming conventions and International Nonproprietary Names.

Creon

In the US, Creon (pancrelipase systemic) is a member of the drug class digestive enzymes and is used to treat Chronic Pancreatitis, Cystic Fibrosis and Pancreatic Exocrine Dysfunction.

US matches:

• Creon


• Creon 10 Delayed-Release Capsules


• Creon 10


• Creon 20


• Creon 5

UK matches:

• Creon 10000
• Creon 25000
• Creon 40000
• Creon Micro
• Creon (SPC)
• Creon 10000 Capsules (SPC)
• Creon 25000 Capsules (SPC)
• Creon 40000 Capsules (SPC)
• Creon Micro (SPC)

Ingredient matches for Creon

Pancreatin

Pancreatin is reported as an ingredient of Creon in the following countries:

• Argentina


• Australia


• Belgium


• Brazil


• Canada


• China


• Finland


• Greece


• Hong Kong


• Iceland


• Ireland


• Israel


• Luxembourg


• Malaysia


• Mexico


• Netherlands


• New Zealand


• Norway


• Peru


• Philippines


• Singapore


• South Africa


• Sweden


• Switzerland


• United Kingdom

Pancrelipase

Pancrelipase is reported as an ingredient of Creon in the following countries:

• Italy


• United States

International Drug Name Search

Glossary

SPC	Summary of Product Characteristics (UK)

Click for further information on drug naming conventions and International Nonproprietary Names.

Acetaminofen La Santé

Acetaminofen La Santé may be available in the countries listed below.

Ingredient matches for Acetaminofen La Santé

Paracetamol

Paracetamol is reported as an ingredient of Acetaminofen La Santé in the following countries:

• Colombia

International Drug Name Search

Valproat Heumann

Valproat Heumann may be available in the countries listed below.

Ingredient matches for Valproat Heumann

Valproic Acid

Valproic Acid sodium (a derivative of Valproic Acid) is reported as an ingredient of Valproat Heumann in the following countries:

• Germany

International Drug Name Search

Nobzol

Nobzol may be available in the countries listed below.

Ingredient matches for Nobzol

Fluconazole

Fluconazole is reported as an ingredient of Nobzol in the following countries:

• Colombia


• Peru

International Drug Name Search

Trasik

Trasik may be available in the countries listed below.

Ingredient matches for Trasik

Tramadol

Tramadol hydrochloride (a derivative of Tramadol) is reported as an ingredient of Trasik in the following countries:

• Indonesia

International Drug Name Search

Sulfaprim

Sulfaprim may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Sulfaprim

Trimethoprim

Trimethoprim is reported as an ingredient of Sulfaprim in the following countries:

• Portugal

International Drug Name Search

Mirtazapin-Teva

Mirtazapin-Teva may be available in the countries listed below.

Ingredient matches for Mirtazapin-Teva

Mirtazapine

Mirtazapine is reported as an ingredient of Mirtazapin-Teva in the following countries:

• Denmark


• Germany

International Drug Name Search

Lamotrigin Heumann

Lamotrigin Heumann may be available in the countries listed below.

Ingredient matches for Lamotrigin Heumann

Lamotrigine

Lamotrigine is reported as an ingredient of Lamotrigin Heumann in the following countries:

• Germany

International Drug Name Search

Apo-Flunisolide

Apo-Flunisolide may be available in the countries listed below.

Ingredient matches for Apo-Flunisolide

Flunisolide

Flunisolide is reported as an ingredient of Apo-Flunisolide in the following countries:

• Canada

International Drug Name Search

Shulander

Shulander may be available in the countries listed below.

Ingredient matches for Shulander

Difenidol

Difenidol hydrochloride (a derivative of Difenidol) is reported as an ingredient of Shulander in the following countries:

• Japan

International Drug Name Search

Prothyrid

Prothyrid may be available in the countries listed below.

Ingredient matches for Prothyrid

Levothyroxine

Levothyroxine sodium salt (a derivative of Levothyroxine) is reported as an ingredient of Prothyrid in the following countries:

• Germany

Liothyronine

Liothyronine sodium salt (a derivative of Liothyronine) is reported as an ingredient of Prothyrid in the following countries:

• Germany

International Drug Name Search

Hytacand

Hytacand may be available in the countries listed below.

Ingredient matches for Hytacand

Candesartan

Candesartan cilexetil (a derivative of Candesartan) is reported as an ingredient of Hytacand in the following countries:

• France


• Portugal


• Tunisia

Hydrochlorothiazide

Hydrochlorothiazide is reported as an ingredient of Hytacand in the following countries:

• France


• Portugal


• Tunisia

International Drug Name Search

Azanin

Azanin may be available in the countries listed below.

Ingredient matches for Azanin

Azathioprine

Azathioprine is reported as an ingredient of Azanin in the following countries:

• Japan

International Drug Name Search

Adant Dispo

Adant Dispo may be available in the countries listed below.

Ingredient matches for Adant Dispo

Hyaluronic Acid

Hyaluronic Acid sodium salt (a derivative of Hyaluronic Acid) is reported as an ingredient of Adant Dispo in the following countries:

• Indonesia


• Thailand

International Drug Name Search

Supatraz

Supatraz may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Supatraz

Amitraz

Amitraz is reported as an ingredient of Supatraz in the following countries:

• South Africa

International Drug Name Search

Coxalgan

Coxalgan may be available in the countries listed below.

Ingredient matches for Coxalgan

Nabumetone

Nabumetone is reported as an ingredient of Coxalgan in the following countries:

• Poland

International Drug Name Search

Endak

Endak may be available in the countries listed below.

Ingredient matches for Endak

Carteolol

Carteolol hydrochloride (a derivative of Carteolol) is reported as an ingredient of Endak in the following countries:

• Germany

International Drug Name Search

Gertac

Gertac may be available in the countries listed below.

Ingredient matches for Gertac

Ranitidine

Ranitidine hydrochloride (a derivative of Ranitidine) is reported as an ingredient of Gertac in the following countries:

• Ireland

International Drug Name Search

Artrixib

Artrixib may be available in the countries listed below.

Ingredient matches for Artrixib

Celecoxib

Celecoxib is reported as an ingredient of Artrixib in the following countries:

• Peru

International Drug Name Search

Supposte Glicerina Carlo Erba

Supposte Glicerina Carlo Erba may be available in the countries listed below.

Ingredient matches for Supposte Glicerina Carlo Erba

Glycerol

Glycerol is reported as an ingredient of Supposte Glicerina Carlo Erba in the following countries:

• Italy

International Drug Name Search

Biodramina

Biodramina may be available in the countries listed below.

Ingredient matches for Biodramina

Dimenhydrinate

Dimenhydrinate is reported as an ingredient of Biodramina in the following countries:

• Costa Rica


• El Salvador


• Guatemala


• Honduras


• Malta


• Nicaragua


• Panama


• Spain

International Drug Name Search

Ventisal

Ventisal may be available in the countries listed below.

Ingredient matches for Ventisal

Salbutamol

Salbutamol sulfate (a derivative of Salbutamol) is reported as an ingredient of Ventisal in the following countries:

• Bangladesh

International Drug Name Search

Clotrimazol Creme-1A Pharma

Clotrimazol Creme-1A Pharma may be available in the countries listed below.

Ingredient matches for Clotrimazol Creme-1A Pharma

Clotrimazole

Clotrimazole is reported as an ingredient of Clotrimazol Creme-1A Pharma in the following countries:

• Germany

International Drug Name Search

Rescriptor

Generic Name: Delavirdine Mesylate
Class: Nonnucleoside Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: 1 - [3 - [(1 - Methylethyl)amino] - 2 - pyridinyl] - 4 - [[5 - [(methylsulfonyl)amino] - 1H - indol - 2 - yl]carbonyl] - piperazinemonomethanesulfonate
Molecular Formula: C₂₂H₂₈N₆O₃S•CH₄ O₃S
CAS Number: 147221-93-0

Introduction

Antiretroviral; nonnucleoside reverse transcriptase inhibitor (NNRTI).^{1 2 3 6 7 8 10 11 12}

Uses for Rescriptor

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.¹

Not generally recommended for use in initial antiretroviral regimens (less potent virologic activity than other NNRTIs, inconvenient dosing).^{2 17 54}

When selecting delavirdine for use in multi-drug regimens for initial therapy, consider that there are insufficient data comparing regimens that include delavirdine to the preferred 3-drug regimens and that the portion of patients who respond to a regimen of delavirdine and 2 nucleoside reverse transcriptase inhibitors (NRTIs) with sustained HIV-1 levels <400 copies/mL may be low.¹

Rescriptor Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.^{1 2 6}

For patients unable to swallow tablets, the 100-mg tablets may be administered as a slurry or dispersion in water.^{1 2 6} To prepare a dispersion containing 400 mg, place four 100-mg tablets in a glass containing ≥90 mL of water, let stand for a few minutes, then stir until a uniform dispersion occurs.^{1 6} The dispersion should be consumed promptly; rinse the glass with more water and swallow the rinse.¹

The 200-mg tablets are not readily dispersed in water^{1 33} and should be swallowed intact.^{1 2}

Patients with achlorhydria should take delavirdine with an acidic beverage (e.g., orange or cranberry juice).¹

Dosage

Available as delavirdine mesylate; dosage expressed in terms of delavirdine mesylate.¹

Must be given in conjunction with other antiretrovirals.¹ If used with certain didanosine preparations, administer drugs at least 1 hour apart; if used with indinavir, adjustment in the treatment regimen necessary.^{1 56} (See Specific Drugs under Interactions.)

Pediatric Patients

Treatment of HIV Infection

Oral

Adolescents ≥16 years of age: 400 mg 3 times daily.^{1 2}

Adults

Treatment of HIV Infection

Oral

400 mg 3 times daily.^{1 2}

Special Populations

Renal Impairment

Dosage adjustments not necessary.²

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Rescriptor

Contraindications

• 
  

  Known hypersensitivity to delavirdine or any ingredient in the formulation.¹

  
  


• 
  

  Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alprazolam, cisapride, ergot alkaloids, midazolam, pimozide, triazolam).¹ (See Specific Drugs under Interactions.)

  
  

Warnings/Precautions

Warnings

Interactions

Concomitant use with certain drugs is not recommended (e.g., lovastatin, simvastatin, rifampin, rifabutin, St. John’s wort) or require particular concern (sildenafil, tadalafil, vardenafil).^{1 2} (See Specific Drugs under Interactions.)

Sensitivity Reactions

Dermatologic Reactions

Severe rash, erythema multiforme, Stevens-Johnson syndrome reported; these severe reactions resolved after drug discontinued.¹

Patients experiencing severe rash or rash accompanied by fever, blistering, oral lesions, conjunctivitis, swelling, or muscle or joint aches should discontinue delavirdine and seek medical assistance.¹

Mild rash also reported.¹ Rash usually occurs during the first month of therapy, mainly on upper body and proximal arms with decreasing intensity of lesions on the neck and face and progressively less on the rest of the trunk and limbs.¹

Rash usually resolves in <2 weeks and generally does not require dosage reduction or contraindicate use of the drug.¹ If delavirdine therapy is interrupted because of rash, most patients are able to resume therapy with the drug.¹

Mild or moderate rash can be treated with diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.¹

General Precautions

HIV Resistance

Possibility of HIV resistant to delavirdine and possible cross-resistance to other NNRTIs.¹

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.¹

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.¹

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.¹

Pediatric Use

Safety and efficacy not established in children <16 years of age.¹

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.¹

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Hepatic Impairment

Extensively metabolized in liver; use with caution in those with hepatic impairment.¹

Common Adverse Effects

Rash; asthenia/fatigue; nausea.¹

Interactions for Rescriptor

Metabolized by CYP3A and CYP2D6.¹

Inhibits CYP3A, and to a lesser extent, CYP2C9, CYP2D6, CYP2C19.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A;¹ possible alteration in metabolism of delavirdine and/or other drug.¹

Specific Drugs

Drug	Interaction	Comments
Amphetamines	Possible increased amphetamine concentrations1	Use with caution1
Antacids (Maalox TC)	Decreased delavirdine concentrations1	Take delavirdine at least 1 hour before or after antacids1 2
Antiarrhythmic agents (amiodarone, flecainide, systemic lidocaine, propafenone, quinidine)	Possible increased antiarrhythmic agent concentrations; potential for serious or life-threatening effects (e.g., cardiac arrhythmias) with certain agents1	Use concomitantly with caution; monitor plasma concentrations of the antiarrhythmic agent1
Anticoagulants, oral	Possible increased warfarin concentrations 1 2	Use concomitantly with caution; monitor INR1
Anticonvulsants (carbamazepine, phenytoin, phenobarbital)	Decreased delavirdine concentrations; possible loss of virologic response and development of resistance to the antiretroviral1	Concomitant use not recommended1 2
Antifungals, azoles (fluconazole, ketoconazole, voriconazole)	Fluconazole: Pharmacokinetic interaction not clinically important1 2
	Itraconazole: Possible pharmacokinetic interaction; may affect both drugs2	Itraconazole: Monitor delavirdine and itraconazole concentrations2
	Ketoconazole: Increased delavirdine concentrations1 2	Ketoconazole: Dosage adjustment not needed2
	Voriconazole: Possible pharmacokinetic interaction;2 53 may affect both drugs2	Voriconazole: Monitor for antiretroviral toxicity and for clinical response to voriconazole2
Antimycobacterials (rifabutin, rifampin, rifapentine)	Rifabutin: Decreased delavirdine AUC; increased rifabutin AUC1 2 Rifampin: Decreased delavirdine AUC 1 2 Possible loss of virologic response and increased risk of delavirdine or NNRTI resistance1	Concomitant use with rifabutin, rifampin, or rifapentine not recommended1 2 34 35
Benzodiazepines (alprazolam, midazolam, triazolam)	Potential for prolonged or increased sedation or respiratory depression1	Concomitant use with alprazolam, midazolam, or triazolam contraindicated;1 2 some experts state a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation2
Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, isradipine, nifedipine, nimodipine, nisoldipine, verapamil)	Possible increased concentrations in the calcium-channel blocking agent1	Use concomitantly with caution; clinical monitoring recommended1
Cisapride	Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1 2
Co-trimoxazole	Interaction unlikely1
Corticosteroids (dexamethasone, fluticasone)	Dexamethasone: Possible decreased delavirdine concentrations 1	Dexamethasone: Use with caution; delavirdine may be less effective1
	Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations resulting in decreased cortisol concentrations1 2	Fluticasone nasal spray/oral inhalation: Use with caution; consider alternative to fluticasone, especially when long-term corticosteroid therapy is anticipated1
Didanosine	Decreased delavirdine concentrations if given at the same time as buffered didanosine preparations;56 clinically important pharmacokinetic interaction not observed when buffered didanosine administered 1 hour after delavirdine;56 pharmacokinetic interaction not expected with didanosine delayed-release tablets57 In vitro evidence of additive or synergistic antiretroviral effects1	Administer at least 1 hour before buffered didanosine (pediatric oral solution admixed with antacid)1 56
Efavirenz		Concomitant use of NNRTIs not recommended2
Emtricitabine	In vitro evidence of additive or synergistic antiretroviral effectsg
Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)	Potential for serious or life-threatening reactions (e.g., acute ergot toxicity)1	Concomitant use contraindicated1 2 If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving delavirdine, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible44
Estrogens/Progestins	Hormonal contraceptives: Possible increased concentrations of ethinyl estradiol1 2	Clinical importance unknown1 2
Etravirine	Possible increased concentrations of etravirine58	Concomitant use of NNRTIs not recommended2 58
Fluoxetine	Increased delavirdine trough concentrations1
Fosamprenavir	Studies using amprenavir indicate possible increased amprenavir concentrations and AUC and possible decreased delavirdine concentrations and AUC;2 a possible decreased antiretroviral efficacy and increased risk of antiretroviral resistancea	Concomitant use not recommended2
Histamine H2-receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine)	Possible decreased GI absorption of delavirdine1	Long-term concomitant use not recommended1 2
HMG-CoA reductase inhibitors	Decreased clearance and increased concentrations of some HMG-CoA reductase inhibitors (lovastatin, simvastatin, atorvastatin, fluvastatin) with potential for increased risk of myopathy (including rhabdomyolysis)1	Concomitant use with lovastatin or simvastatin not recommended1 2 If used with atorvastatin or fluvastatin, use lowest possible dosage of the HMG-CoA reductase inhibitor1 Consider using HMG-CoA reductase inhibitors with a low potential for interaction (e.g., pravastatin )1
Immunosuppressive agents (cyclosporine, rapamycin, tacrolimus)	Potential for increased concentrations of cyclosporine, rapamycin, or tacrolimus1	Monitor plasma concentrations of the immunosuppressive agent1
Indinavir	No change in pharmacokinetics of delavirdine; increased peak plasma concentrations and AUC of indinavir1 2 32	When given with delavirdine 400 mg 3 times daily (usual delavirdine dosage), reduce indinavir dosage to 600 mg every 8 hours1 2 32
Lamivudine	In vitro evidence of additive or synergistic antiretroviral effects1
Lopinavir	Possible increased lopinavir concentrations1 46	Appropriate dosages for concomitant use with respect to safety and efficacy not established1 46
Macrolides (clarithromycin)	No change in pharmacokinetic of delavirdine; increased AUC of clarithromycin1	Dosage adjustment not needed in patients with normal renal function; reduce clarithromycin dosage by 50% in patients with Clcr 30–60 mL/minute and by 75% in patients with Clcr <30 mL/minute1
Maraviroc	Possible increased concentrations of maraviroc2	Recommended dosage of maraviroc is 150 mg twice daily2
Methadone	Possible increased methadone concentrations;1 2 no change in delavirdine concentrations2	Monitor for methadone toxicity;2 consider need to decrease methadone dosage1 2
Nelfinavir	Increased nelfinavir concentrations; decreased delavirdine concentrations1 2 c Increased toxicity (i.e., neutropenia) observed1 2 45 In vitro evidence of synergistic antiretroviral effectsc	Appropriate dosage for concomitant use not established1 2 c Monitor neutrophil counts, especially during first few months of therapy2
Nevirapine		Concomitant use of NNRTIs not recommended2
Pimozide	Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1
Proton-pump inhibitors (omeprazole, lansoprazole)	Possible decreased GI absorption of delavirdine1	Long-term concomitant use not recommended1
Quinupristin and dalfopristin	Possible increased delavirdine concentrations39
Ritonavir	Increased ritonavir concentrations;1 2 no change in delavirdine concentrations2	Appropriate dosage for concomitant use not established1 2
Saquinavir	Increased saquinavir concentrations;1 2 48 no effect on delavirdine concentrations1 Concomitant use with ritonavir-boosted saquinavir not evaluated48	Some clinicians recommend using saquinavir 1 g twice daily and ritonavir 100 mg twice daily with usual dosage of delavirdine2 Manufacturer of saquinavir states appropriate dosages for concomitant use with respect to safety and efficacy not established48
St. John’s wort (Hypericum perforatum)	Possible loss of virologic response and increased risk of delavirdine or NNRTI resistance1	Concomitant use not recommended1 2
Sildenafil	Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)1 2	Use caution and reduced sildenafil dosage; do not exceed 25 mg once in 48 hours1 2
Tadalafil	Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)2	Use caution and reduced tadalafil dosage; do not exceed 5 mg once in 72 hours2
Tenofovir	In vitro evidence of additive or synergistic antiretroviral effectsb
Tipranavir	In vitro evidence of additive antiretroviral effectsf
Trazodone	Possible increased trazodone concentrations1 Adverse effects (nausea, dizziness, hypotension, syncope) reported with concomitant use of trazodone and other CYP3A inhibitors (e.g., ritonavir)1	Use with caution; consider using decreased trazodone dosage1
Vardenafil	Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)2	Use caution and reduced vardenafil dosage; do not exceed 2.5 mg once in 24 hours2
Zidovudine	Pharmacokinetic interaction unlikely1 6 In vitro evidence of additive or synergistic antiretroviral effects1

Rescriptor Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract; peak plasma concentrations achieved within 1 hour.¹

Bioavailability of delavirdine tablets is 85% relative to that of an oral solution of the drug.¹ Bioavailability of the 100-mg tablets is increased by approximately 20% when the tablets are allowed to disintegrate in water and administered as a slurry.¹

Food

Food does not have an appreciable effect on plasma concentrations or AUC.¹

Distribution

Extent

Not fully characterized.¹

Distributed into CSF in low concentrations.¹

Plasma Protein Binding

98%.¹

Elimination

Metabolism

Metabolized by CYP3A and CYP2D6.¹

Elimination Route

Excreted in feces (44%) and urine (51%).¹

Half-life

5.8 hours.¹

Stability

Storage

Oral

Tablets

20–25°C in tight container; protect from high humidity.¹

Actions and SpectrumActions

• 
  

  Pharmacologically related to other NNRTIs (e.g., efavirenz, etravirine. nevirapine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.^{1 6 7 8 10 11 12 58}

  
  


• 
  

  Active against HIV-1; inactive against HIV-2.^{1 8 31}

  
  


• 
  

  Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.^{1 6 7 8 10 11 12 15}

  
  


• 
  

  HIV-1 with reduced susceptibility to delavirdine have been selected in vitro and have emerged during therapy with the drug.^{1 6 8 19 31}

  
  


• 
  

  Strains of HIV-1 resistant to delavirdine may be cross-resistant to some other NNRTIs.^{1 6 7}

  
  


• 
  

  Cross-resistance between delavirdine and NRTIs unlikely since the drugs bind at difference sites on reverse transcriptase and have difference mechanisms of action.^{1 15} Cross-resistance between delavirdine and HIV protease inhibitors (PIs) unlikely since the drugs have different target enzymes and mechanisms of action.¹

  
  

Advice to Patients

• 
  

  Critical nature of compliance with HIV therapy.¹ Importance of using delavirdine in conjunction with other antiretrovirals— not for monotherapy.¹

  
  


• 
  

  Antiretroviral therapy is not a cure for HIV infection, and opportunistic infections still may occur.¹ HIV transmission via sexual contact or sharing needles is not prevented by antiretrovirals.¹

  
  


• 
  

  Importance of discontinuing delavirdine and consulting a clinician if severe rash or rash accompanied by fever, blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches occurs.¹

  
  


• 
  

  Importance of reading patient package insert from manufacturer.¹

  
  


• 
  

  Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.¹

  
  


• 
  

  Importance of patients with achlorhydria taking delavirdine with an acidic beverage.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Delavirdine Mesylate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	100 mg	Rescriptor	Pfizer
		200 mg	Rescriptor	Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Rescriptor 200MG Tablets (VIIV HEALTHCARE): 30/$59.99 or 90/$170.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions September 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer. Rescriptor (delavirdine mesylate) tablets prescribing information. New York, NY; 2008 May.

2. Panel on Antiretroviral Guidelines for Adults and Adolescents of the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (November 3, 2008). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

3. Centers for Disease Control and Prevention. Report of the NIH panel to define principles of therapy of HIV infection. MMWR Morb Mortal Wkly Rep. 1998; 47(No. RR-5):1-42. [PubMed 9450721]

4. Para MF, Meehan P, Holden-Wiltse J et al. ACTG 260: a randomized, phase I-II, dose-ranging trial of anti-human immunodeficiency virus activity of delavirdine monotherapy. Antimicrob Agents Chemother. 1999; 43:1373-8. [IDIS 426249] [PubMed 10348755]

5. Friedland GH, Pollard R, Griffith B et al. Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease and CD4 counts of 100 to 500 cells/mm³ (ACTG 261). J Acquir Immune Defic Syndr. 1999; 21:281-92. [IDIS 431632] [PubMed 10428106]

6. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.

7. Moyle GJ. Resistance to antiretroviral compounds: implications for the clinical management of HIV infection. Immunol Infect Dis. 1995; 5:170-82.

8. Freimuth WW. Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor. Antiviral Chemother. 1996; 4:279-89.

9. Dueweke TJ, Poppe SM, Romero DL et al. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother. 1993; 37:1127-31. [PubMed 7685995]

10. Althaus IW, Chou JJ, Gonzales AJ et al. Steady-state kinetic studies with the non-nucleoside HIV-1 reverse transcriptase inhibitor U-87201E. J Biol Chem. 1993; 268:6119-24. [PubMed 7681060]

11. Althaus IW, Chou JJ, Gonzales AJ et al. Kinetic studies with the non-nucleoside human immunodeficiency virus type-1 reverse transcriptase inhibitor U-90152E. Biochem Pharmacol. 1994; 47:2017-28. [PubMed 7516658]

12. Dueweke TJ, Kezdy FJ, Waszak GA et al. The binding of a novel bisheteroarylpiperazine mediates inhibition of human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem. 1992; 267:27-30. [PubMed 1370445]

13. Watkins BA, Klotman ME, Gallo RC. Human Immunodeficiency Viruses. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone; 1995:1590-606.

14. Sardana VV, Emini EA, Gotlib L et al. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J Biol Chem. 1992; 267:17526-30. [PubMed 1381350]

15. Gu Z, Quan Y, Li Z et al. Effects of nonnucleoside inhibitors of human immunodeficiency virus type 1 in cell-free recombinant reverse transcriptase assays. J Biol Chem. 1995; 270:31046-51. [PubMed 8537362]

16. Vasudevachari MB, Battista C, Lane HC et al. Prevention of the spread of HIV-1 infection with nonnucleoside reverse transcriptase inhibitors. Virology. 1992; 190:269-77. [PubMed 1382341]

17. Hammer SM, Saag MS, Schechter M et al. Treatment of adult HIV infection: 2006 recommendations of the International AIDS Society–USA panel. JAMA. 2006; 296:827-43. [PubMed 16905788]

18. Chong KT, Pagano PJ. Inhibition of human immunodeficiency virus type 1 infection in vitro by combination of delavirdine, zidovudine and didanosine. Antiviral Res. 1997; 34:51-63. [PubMed 9107385]

19. Demeter LM, Meehan PM, Morse G et al. HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine. J Acquir Immune Defic Syndr. 1997; 14:136-44.

20. Kohlstaedt LA, Wang J, Friedman JM et al. Crystal structure at 3.5 resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 1992; 256:1783-90. [PubMed 1377403]

21. Spence RA, Kati WM, Anderson KS et al. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science. 1995; 267:988-93. [PubMed 7532321]

22. Morse GD, Fischl MA, Shelton MJ et al. Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1997; 41:169-74. [IDIS 378388] [PubMed 8980774]

23. Bellman PC. Clinical experience with adding delavirdine to combination therapy in patients in whom multiple antiretroviral treatment including protease inhibitors had failed. AIDS. 1998; 12:1333-40. [PubMed 9708413]

24. Agouron Pharmaceuticals, La Jolla, CA: Personal communication on nelfinavir 8:18.

25. Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children of the National Resource Center at the François-Xavier Bagnoud Center, Health Resources and Services Administration (HRSA), and National Institutes of Health (NIH). Guidelines for the use of antiretroviral agents in pediatric HIV infection (February 23, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

26. AIDS Clinical Trials Information Service (ACTIS) (database). 2000 Jun. From web site.

27. Barin F, Couroue AM, Pillonel J et al. Increasing diversity of HIV-1_M serotypes in French blood donors over a 10-year period (1985-1995). AIDS. 1997; 11:1503-8. [PubMed 9342073]

28. Shelton MJ, Hewitt RG, Adams JM et al. Delavirdine (DLV) mesylate pharmacokinetics (PK) during combination therapy with ritonavir (RIT). Proceedings of the 37th ICAAC. Toronto 1997. Abstract No A-63.

29. Pharmacia & Upjohn. Interim analysis protocol 0021, Part II. Kalamazoo, MI; 1997 Oct.

30. Reviewers’ comments (personal observations).

31. Witvrouw M, Pannecourque C, Van Laethem K et al. Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV. AIDS. 1999; 13:1477-83. [PubMed 10465070]

32. Merck & Company Inc. Crixivan (indinavir sulfate) capsules prescribing information. Whitehouse Station, NJ; 2004 May.

33. Rohrs BR, Thamann TJ, Gao P et al. Tablet dissolution affected by a moisture mediated solid-state interaction between drug and disintegrant. Pharm Res. 1999; 16:1850-6. [PubMed 10644073]

34. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations MMWR. 1998; 47(No. RR-20).

35. Centers for Disease Control and Prevention. Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR Morb Mortal Wkly Rep. 2000; 49:185-9. [IDIS 441965] [PubMed 11795500]

36. Borin MT, Cox SR, Herman BD et al. Effect of fluconazole on the steady-state pharmacokinetics of delavirdine in human immunodeficiency virus-positive patients. Antimicrob Agents Chemother. 1997; 41:1892-7. [IDIS 393391] [PubMed 9303380]

37. Demeter LM, Shafer RW, Meehan PM et al. Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260). Antimicrob Agents Chemother. 2000; 44:794-7. [IDIS 442146] [PubMed 10681363]

38. Mills G, Morgan J, hales G et al. Acute hypersensitivity with delavirdine. Antivir Ther. 1999; 4:51. [PubMed 10682129]

39. Rhone-Poulenc Rorer Pharmaceuticals Inc. Synercid I.V. (quinupristin and dalfopristin) prescribing information. Collegeville, PA; 1999 Jul.

40. Lumpkin MM, Alpert A. Risk of drug interactions with St. John’s wort and indinavir and other drugs. FDA Public Health Advisory. 2000 Feb 10. From FDA website.

41. Piscitelli SC, Burstein AH, Chaitt D et al. Indinavir concentrations and St. John’s wort. Lancet. 2000; 355:547-8. [IDIS 440260] [PubMed 10683007]

42. Johne A, Brockmoller J, Bauer S et al. Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s wort (Hypericum perforatum). Clin Pharmacol Ther. 1999; 66:338-45. [IDIS 435511] [PubMed 10546917]

43. Ruschitzka F, Meier PJ, Turina M et al. Acute heart transplant rejection due to Saint John’s wort. Lancet. 2000; 355:548-9. [IDIS 440261] [PubMed 10683008]

44. Perinatal HIV Guidelines Working Group. Public Health Service task force recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States (April 29, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

45. Yuen N (Agouron Pharmaceuticals, La Jolla, CA). Personal communication; 2000 Aug 4.

46. Abbott. Kaletra (lopinavir/ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2005 Oct.

47. American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infections. Am J Respir Crit Care Med. 2000; 161:S221-47.

48. Roche Laboratories. Invirase (saquinavir mesylate) capsules prescribing information. Nutley, NJ; 2005 Sep.

49. Hood R, Hawkins DA, Moyle G et al. Second placebo-controlled study in naive individuals confirms the role of delavirdine in highly active antiretroviral, protease-sparing treatment. Proceedings of the 6th Conference on Retroviruses and Opportunistic Infections. Chicago, IL: 1999.

50. Moyle G, De Cian W, Hawkins D et al. Final 54-week analysis of a placebo-controlled trial (13C) of delavirdine (DLV) plus two nucleoside analogs (NA) versus two NA in drug-naïve and -experienced individuals. Proceedings of the 39th ICAAC. San Francisco, CA: 1999.

51. Gulick RM, Hus XJ, Fiscus SA et al. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS clinical trials group study 359. J Infect Dis. 2000; 182:1375-84. [IDIS 455265] [PubMed 11023461]

52. Smith D, Hales G, Roth N et al. A randomized trial of nelfinavir, ritonavir, or delavirdine in combination with saquinavir-SGC and stavudine in treatment-experienced HIV-1-infected patients. HIV Clin Trials. 2001; 2:97-107. [PubMed 11590517]

53. Pfizer. Vfend (voriconazole) for injection, tablets, and for oral suspension prescribing information. New York, NY; 2003 Dec.

54. Gazzard B, for the BHIVA Guidelines Writing Committee. British HIV association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005). HIV Med. 2005; 6(Suppl 2):1-61.

55. GlaxoSmithKline. Agenerase (amprenavir) capsules prescribing information. Research Triangle Park, NC; 2005 May.

56. Bristol-Myers Squibb. Videx (didanosine) pediatric powder for oral solution prescribing information. Princeton, NJ; 2006 Feb.

57. Bristol-Myers Squibb. Videx EC (didanosine) delayed-release capsules enteric-coated beadlets prescribing information. Princeton, NJ; 2006 Feb

58. Tibotec Therapeutics. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2008 Jan.

a. GlaxoSmithKline. Lexiva (fosamprenavir calcium) tablets prescribing information. Research Triangle Park, NC; 2005 Nov.

b. Gilead Sciences Inc. Viread (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2004 Jun.

c. Agouron Pharmaceuticals. Viracept (nelfinavir mesylate) tablets and oral powder prescribing information. La Jolla, CA; 2004 Sept.

f. Boehringer Ingelheim. Aptivus (tipranavir) capsules prescribing information. Ridgefield, CT; 2005 Jun

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Romidepsin

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13, dithia-5,8,20,23-tetraazabicyclo[8,7,6]tricos-16-ene-3,6,9,19,22-pentone.
Molecular Formula: C₂₄H₃₆N₄O₆S₂
CAS Number: 128517-07-7
Brands: Istodax

Introduction

Antineoplastic agent; a histone deacetylase (HDAC) inhibitor. ^{1 15}

Uses for Romidepsin

Cutaneous T-cell Lymphoma

Treatment of cutaneous T-cell lymphoma (CTCL; e.g., mycosis fungoides, Sézary syndrome) in adult patients who have received at least 1 prior systemic therapy.^{1 3 4 15}

Designated an orphan drug by the FDA for use in this condition.²

Romidepsin Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

  
  


• 
  

  Serum concentrations of potassium and magnesium should be within the normal range prior to romidepsin administration.^{1 3} (See Electrolyte Monitoring under Cautions.)

  
  


• 
  

  Prophylactic antiemetics were administered to prevent nausea in romidepsin-treated patients in clinical trials.^{3 6}

  
  

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.¹

Administer by IV infusion only.¹

Romidepsin is commercially available as a kit that includes a single-use vial containing 10 mg of romidepsin and a sterile vial containing 2 mL of diluent (composed of 80% propylene glycol and 20% dehydrated alcohol).¹

Reconstitution

Based on the indicated dosage, reconstitute each of the appropriate number of vials labeled as containing 10 mg of romidepsin with 2 mL of supplied diluent to provide a solution containing 5 mg/mL.¹ Swirl vials until no visible particles are present in the resulting solution.¹ Must be further diluted before IV administration.¹

Dilution

Following reconstitution, add the appropriate volume of drug to 500 mL of 0.9% sodium chloride injection in a suitable container. (See Storage under Stability.)¹

Rate of Administration

Administer by IV infusion over 4 hours.¹

Dosage

Adults

Cutaneous T-cell Lymphoma

IV

14 mg/m² (by IV infusion) on days 1, 8, and 15 of a 28-day cycle.^{1 3 4} Repeat cycles every 28 days as long as the patient derives benefit and tolerates therapy.¹

Optimal duration of treatment not clearly established; therapy was continued for ≤83 months in clinical trials.^{1 3 4}

Dosage Modification for Toxicity

Depending on severity of toxicity, may need to delay therapy and/or reduce subsequent dosages or discontinue drug permanently.¹ Dosages reduced following drug-related adverse effects should not be re-escalated.¹

Non-hematologic Toxicity (Except Alopecia)

Grade 2 or 3 toxicity: Delay therapy until toxicity returns to ≤grade 1 or to baseline.¹ Then may restart at 14 mg/m².¹ If grade 3 toxicity recurs, delay romidepsin until toxicity returns to ≤grade 1 or baseline and permanently reduce dosage to 10 mg/m².¹

Grade 4 toxicity: Delay therapy until toxicity returns to ≤grade 1 or to baseline and permanently reduce dosage to 10 mg/m².¹

Discontinue therapy if grade 3 or 4 toxicities recur after dosage reduction.¹

Hematologic Toxicity

Grade 3 or 4 neutropenia or thrombocytopenia: Delay therapy until specific cytopenia returns to ANC ≥1500 cells/mm³ and/or a platelet count of ≥75,000 cells/mm³ or to baseline.¹ Then may restart at 14 mg/m².¹

Grade 4 febrile neutropenia (temperature ≥38.5°C) or thrombocytopenia requiring a platelet transfusion: Delay therapy until specific cytopenia returns to ≤grade 1 or to baseline and permanently reduce dosage to 10 mg/m².¹

Special Populations

Hepatic or Renal Impairment

Routine dosage adjustment not necessary in patients with hepatic or renal impairment; however, consider that pharmacokinetics may be altered.¹ (See Hepatic Impairment under Cautions and see also Renal Impairment under Cautions.)

Cautions for Romidepsin

Contraindications

• 
  

  No known contraindications.¹

  
  

Warnings/Precautions

Electrolyte Monitoring

Patients with CTCL are at risk of hypomagnesemia.^{3 9} Because of the risk of QT prolongation and other ECG abnormalities associated with hypomagnesemia and hypokalemia as well as with HDAC inhibitor therapy (including romidepsin), serum concentrations of potassium and magnesium should be within the normal range prior to romidepsin administration.^{1 3} Also consider electrolyte and ECG monitoring at baseline and periodically during romidepsin therapy in patients at high risk for QT-interval prolongation (see ECG Changes under Cautions).¹

Hematologic Effects

Risk of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia.¹ Monitor these hematologic parameters during therapy and adjust dosage if necessary.¹ (See Dosage Modification for Toxicity under Dosage and Administration.)

ECG Changes

Treatment-related ECG changes, including T-wave and ST-segment changes, reported.^{1 6 7} May also prolong QT interval; further studies needed.^{1 3 6 7 15} Clinical importance of these ECG changes unknown.¹

Consider appropriate cardiovascular monitoring precautions (e.g., monitor electrolytes and ECG at baseline and periodically during therapy) in patients with congenital long QT syndrome, those with a history of substantial cardiovascular disease, and those taking antiarrhythmic drugs or other agents that can cause clinically important QT-interval prolongation. ¹ (See Electrolyte Monitoring under Cautions and see also Drugs that Prolong QT Interval under Interactions.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;¹ a study in rats did not expose pregnant animals to enough romidepsin to fully evaluate possible adverse outcomes.¹ (See Advice to Patients.)

Interactions with Estrogen-containing Contraceptives

An in vitro binding assay demonstrated that romidepsin competes with β-estradiol for binding to estrogen receptors.^{1 15} May reduce effectiveness of estrogen-containing contraceptives (e.g., oral contraceptives, patches, implants, IUDs), possibly resulting in pregnancy.^{1 15} (See Advice to Patients.)

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into human milk; discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹ (See Special Populations under Pharmacokinetics.)

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

Mild hepatic impairment does not substantially affect pharmacokinetics of romidepsin.¹ Effects of moderate and severe hepatic impairment on pharmacokinetics of romidepsin not known; use with caution in patients with moderate or severe hepatic impairment.¹

Renal Impairment

Pharmacokinetics have not been formally studied in patients with renal impairment and end-stage renal disease (see Special Populations under Pharmacokinetics).¹ Use with caution in patients with end-stage renal disease.¹

Common Adverse Effects

Nausea,^{1 3 4} asthenia/fatigue,^{1 3 4} infections,^{1 3} vomiting,^{1 3 4} anorexia,^{1 3 4} hypomagnesemia,^{1 3 4} diarrhea,¹ pyrexia,^{1 4} anemia,^{1 3} thrombocytopenia,^{1 3} dysgeusia,^{1 3} constipation,¹ neutropenia,^{1 3} hypotension,¹ pruritus,^{1 4} hypokalemia,¹ dermatitis/exfoliative dermatitis,¹ hypocalcemia,^{1 3} leukopenia, ^{1 3} lymphopenia,^{1 3} elevated transaminase concentrations,^{1 3} hypoalbuminemia,^{1 3} ECG changes (ST-T wave changes), ¹ hyperglycemia,^{1 3} hyponatremia,¹ hypermagnesemia,¹ hypophosphatemia,¹ and hyperuricemia.^{1 3}

Interactions for Romidepsin

Metabolized principally by CYP3A4, and to a lesser extent, by CYP3A5, CYP1A1, CYP2B6, and CYP2C19.^{1 15 22}

Does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.¹

Substrate of P-glycoprotein.^{1 10 11 15}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: potential pharmacokinetic interaction (increased plasma romidepsin concentrations).¹ Avoid concomitant use with strong CYP3A4 inhibitors, if possible.^{1 15} Use caution during concomitant administration of moderate CYP3A4 inhibitors.¹

Inducers of CYP3A4: potential pharmacokinetic interaction (decreased plasma romidepsin concentrations).¹ Avoid concomitant use with strong CYP3A4 inducers, if possible.¹

Drugs Affecting P-glycoprotein Transport

Inhibitors of P-glycoprotein: potential pharmacokinetic interaction (increased plasma romidepsin concentrations likely).^{1 15} Use with caution.¹

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use of other drugs known to prolong the corrected QT (QT_c) interval. (See ECG Changes under Cautions.)

Specific Drugs

Drug	Interaction	Comments
Amprenavir (no longer commercially available in US)	Possible increased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
Antiarrhythmic agents (class IA [e.g., quinidine, procainamide]; class III [e.g., amiodarone, sotalol])	Possible additive effect on QT-interval prolongation1 17 18 19 20	Avoid concomitant use1
Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole)	Possible increased plasma concentrations of romidepsin 1	Avoid concomitant use, if possible1
Antipsychotic agents (e.g., asenapine, chlorpromazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, thioridazine, ziprasidone)	Possible additive effect on QT-interval prolongation1 17 18 19 20	Avoid concomitant use1
Atazanavir	Possible increased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
Carbamazepine	Possible decreased plasma concentrations of romidepsin1 15	Avoid concomitant use, if possible1
Clarithromycin	Possible increased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
Coumarin-derivative anticoagulants	Prolongation of PT and elevated INR reported during concomitant administration; not systematically evaluated1 14	Carefully monitor PT and INR during concurrent administration1
Dexamethasone	Possible decreased plasma concentrations of romidepsin1 15	Avoid concomitant use, if possible1
Erythromycin	Possible increased plasma romidepsin concentrations1 15	Use with caution1
Estrogen-containing contraceptives (e.g., birth control pills, patches, implants, or IUDs	Possible reduced efficacy of estrogen-containing contraceptives, possibly resulting in pregnancy1 15	Advise women of childbearing potential of possible decreased efficacy of estrogen-containing contraceptives while receiving romidepsin1
5-HT3 receptor antagonists	Possible additive effect on QT-interval prolongation1 17 18 19 20	If concomitant 5-HT3 receptor antagonist is necessary, granisetron is recommended by some clinicians6
Indinavir	Possible increased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
Nefazodone	Possible increased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
Nelfinavir	Possible increased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
Phenobarbital	Possible decreased plasma concentrations of romidepsin1 15	Avoid concomitant use, if possible1
Phenytoin	Possible decreased plasma concentrations of romidepsin1 15	Avoid concomitant use, if possible1
Quinolones (e.g., gatifloxacin, moxifloxacin)	Possible additive effect on QT-interval prolongation1 17 18 19 20	Avoid concomitant use1
Rifabutin, Rifampin, Rifapentine	Possible decreased plasma concentrations of romidepsin1 15	Avoid concomitant use, if possible1
Ritonavir	Possible increased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
Saquinavir	Possible increased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
St. John's Wort (Hypericum perforatum)	Possible decreased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
Telithromycin	Possible increased plasma concentrations of romidepsin1	Avoid concomitant use, if possible1
Tetrabenazine	Possible additive effect on QT-interval prolongation1 17 18 19 20	Avoid concomitant use1

Romidepsin Pharmacokinetics

Absorption

Exhibits linear pharmacokinetics across dosages ranging from 1–24.9 mg/m² when given as an IV infusion over 4 hours in patients with advanced cancers.^{1 22} No accumulation of plasma romidepsin concentrations observed after repeated dosing.¹

Distribution

Extent

Not known whether distributed into human milk.¹

Plasma Protein Binding

92–94% (mainly to α₁-acid glycoprotein).¹

Elimination

Metabolism

Extensively metabolized, principally by CYP3A4 and, to a lesser extent, by CYP3A5, CYP1A1, CYP2B6, and CYP2C19.^{1 15 22}

Half-life

Terminal half-life is approximately 3 hours.^{1 22}

Special Populations

In a population pharmacokinetic analysis, pharmacokinetics of romidepsin not substantially affected by mild hepatic impairment.¹

In a population pharmacokinetic analysis, pharmacokinetics not substantially affected by mild (Cl_cr of 50–80 mL/minute), moderate (Cl_cr of 30–50 mL/minute), or severe (Cl_cr <30 mL/minute) renal impairment.¹ Effect of end-stage renal disease on romidepsin pharmacokinetics not studied.¹

Age, gender, or race did not appear to affect the pharmacokinetics of romidepsin in a population pharmacokinetic analysis.¹ In a limited number of pediatric patients (aged from 2–21 years), pharmacokinetics of romidepsin were similar to those reported in adults in a phase I trial.¹⁴

Stability

Storage

Parenteral

Powder for Injection

Store commercially available kit containing romidepsin vial and diluent vial in the original carton at 20–25°C (may be exposed to 15–30°C).¹

Reconstituted solutions with concentrations of 5 mg/mL are stable at room temperature for up to 8 hours.¹ Diluted solutions are stable at room temperature for up to 24 hours, but should be administered as soon after dilution as possible.¹ Diluted romidepsin solution is compatible in polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), and polyethylene (PE) infusion bags and glass bottles.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility¹

Compatible
Sodium chloride 0.9%

ActionsActions

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  Histone deacetylase (HDAC) inhibitor; antineoplastic agent.^{1 10 11} Bicyclic depsipeptide isolated from the bacterium Chromobacterium violaceum.^{1 10 11}

  
  


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  Precise mechanism of antineoplastic effect not fully characterized.¹ However, HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in modulation of gene expression.^{1 11} HDACs also deacetylate non-histone proteins, such as transcription factors.^{1 11 13}

  
  


• 
  

  In vitro, romidepsin restores the acetylation of histones, resulting in accumulation of acetylated histones, and induces cell cycle arrest and apoptosis in some cancer cell lines with IC₅₀ (concentration of the drug required to inhibit cell growth by 50%) values in the nanomolar range.^{1 11}

  
  

Advice to Patients

• 
  

  Importance of instructing patients to read the patient information carefully before starting therapy and before each treatment.¹

  
  


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  Importance of instructing patients to report excessive nausea or vomiting.¹

  
  

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  Risk of low blood cell counts.¹ Importance of informing patient that regular blood tests will be performed during therapy and of notifying a clinician if unusual bleeding or bruising, tiredness, pallor, shortness of breath, infection, fever, cough, flu-like symptoms, burning on urination, muscle aches, and/or worsening of skin problems occurs.¹

  
  


• 
  

  Risk of ECG changes; importance of informing patient that an ECG test may be performed as needed to check for possible changes.¹ Importance of notifying clinician immediately if abnormal heartbeat, chest pain, or shortness of breath occurs. ¹

  
  

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  Importance of informing women of childbearing potential that romidepsin may reduce effectiveness of estrogen-containing contraceptives (e.g., birth control pills, patches, implants, IUDs).^{1 15}

  
  

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  Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Advise pregnant women of potential risk to the fetus.¹

  
  

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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., anticoagulants, estrogen-containing contraceptives) and OTC drugs and herbal supplements, as well as any concomitant illnesses.¹

  
  

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  Importance of informing patients of other important precautionary information.¹

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Romidepsin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion only	10 mg	Istodax (available as kit with single-use vial of romidepsin and a vial of diluent [containing 80% propylene glycol and 20% dehydrated alcohol])	Celgene

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Celgene Corporation. Istodax (romidepsin) for injection prescribing information. Summit, NJ; 2009 Nov.

2. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD. From FDA website (); accessed 2010 Jul 1.

3. Piekarz RL, Frye R, Turner M et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009; 27:5410-7. [PubMed 19826128]

4. Kim Y, Whittaker S, Demierre MF et al. Clinically significant responses achieved with romidepsin in treatment-refractory cutaneous T-cell lymphoma: final results from a phase 2B international, multicenter, registration study. Blood 2008;112: Abstr. No. 263. Presented at the 50th Annual ASH Meeting. San Francisco, CA: 2008 Dec 6-9.

5. Kim Y, Demierre MF, Kim EJ et al. Clinically significant responses achieved with romidepsin in 37 patients with cutaneous T-cell lymphoma (CTCL) with blood involvement. Blood 2009; 114: Abstr. No. 2683. Presented at the 51st Annual ASH Meeting. New Orleans, LA: 2009 Dec 5-8.

6. Piekarz RL, Frye AR, Wright JJ et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res. 2006; 12:3762-73. [PubMed 16778104]

7. Cabell C, Bates S, Piekarz R et al. Systematic assessment of potential cardiac effects of the novel histone deacetylase (HDAC) inhibitor romidepsin. Blood 2009; Abstr. No. 3709. Presented at the 51st Annual ASH Meeting. New Orleans, LA: 2009 Dec 5-8.

8. US Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry. E14 Clinical Evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 2005 Oct. Accessed at FDA website at .

9. Morgan M, Maloney D, Duvic M. Hypomagnesemia and hypocalcemia in mycosis fungoides: a retrospective case series. Leuk Lymphoma. 2002; 43:1297-302. [PubMed 12152999]

10. Lech-Maranda E, Robak E, Korycka A et al. Depsipeptide (FK228) as a novel histone deacetylase inhibitor: mechanism of action and anticancer activity. Mini Rev Med Chem. 2007; 7:1062-9. [PubMed 17979809]

11. Konstantinopoulos PA, Vandoros GP, Papavassiliou AG. FK228 (depsipeptide): a HDAC inhibitor with pleiotropic antitumor activities. Cancer Chemother Pharmacol. 2006; 58:711-5. [PubMed 16435156]

12. Blagosklonny MV, Robey R, Sackett DL et al. Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity. Mol Cancer Ther. 2002; 1:937-41. [PubMed 12481415]

13. Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009; 27:5459-68. [PubMed 19826124]

14. Fouladi M, Furman WL, Chin T et al. Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children's Oncology Group report. J Clin Oncol. 2006; 24:3678-85.

15. Anon. Romidepsin (Istodax) for cutaneous T-cell lymphoma. Med Lett Drugs Ther. 2010; 52:42-3. [PubMed 20508581]

16. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Zolinza (vorinostat) capsules prescribing information. Whitehouse Station, NJ; 2010 Feb.

17. Schering-Plough. Saphris (asenapine maleate) sublingual tablets prescribing information. Kenilworth, NJ; 2010 Jun.

18. Ortho-McNeil-Janssen Pharmaceuticals. Invega (paliperidone) extended-release tablets prescribing information. Titusville, NJ; 2010 Jan.

19. Stöllberger C, Huber JO, Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol. 2005; 20:243-51.

20. Lundbeck Inc. Xenazine (tetrabenazine) tablets prescribing information. Deerfield, IL; 2009 Sep.

21. Klimek VM, Fircanis S, Maslak P et al. Tolerability, pharmacodynamics, and pharmacokinetic studies of depsipepide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res. 2008; 14:826-32.

22. Woo S, Gardner ER, Chen X et al. Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphomas and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009; 15:1496-503.

23. Celgene Corporation. Summit, NJ: Personal communication.

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