DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Incivek (Telaprevir) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

Potential for INCIVEK to Affect Other Drugs

INCIVEK is an inhibitor of CYP3A. Co-administration of INCIVEK with drugs that are primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions (see Table 5). INCIVEK is also an inhibitor of P-gp. Co-administration of INCIVEK with drugs that are substrates for P-gp transport may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions (see Table 5). If dose adjustments of concomitant medications are made during INCIVEK treatment, they should be re-adjusted after administration of INCIVEK is completed.

Potential for Other Drugs to Affect INCIVEK

INCIVEK is a substrate of CYP3A and P-gp; therefore, drugs that induce CYP3A and/or P-gp may decrease INCIVEK plasma concentrations and reduce the therapeutic effect of INCIVEK. Co-administration of INCIVEK with drugs that inhibit CYP3A and/or P-gp may increase INCIVEK plasma concentrations.

Established and Other Potentially Significant Drug Interactions

Table 5 provides effect of concentration of INCIVEK or concomitant drug with INCIVEK. These recommendations are based on either drug interaction trials (indicated with *) or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.

Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction [See Clinical Pharmacology (Tables 6 and 7) for Magnitude of Interaction.]
Concomitant Drug Class:
Drug Name
Effect on concentration of INCIVEK or Concomitant Drug Clinical Comment
The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK.
ANTIARRHYTHMICS
lidocaine (systemic), amiodarone, bepridil, flecainide, propafenone, quinidine
↑ antiarrhythmics
Co-administration with telaprevir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir.
digoxin 1 ↑ digoxin
Concentrations of digoxin were increased when co-administered with telaprevir. The lowest dose of digoxin should be initially prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
ANTIBACTERIALS
clarithromycin
erythromycin
telithromycin
↑ telaprevir
↑ antibacterials
Concentrations of both telaprevir and the antibacterial may be increased during co-administration. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir. QT interval prolongation and Torsade de Pointes have been reported with clarithromycin and erythromycin. QT interval prolongation has been reported with telithromycin.
ANTICOAGULANT
warfarin ↑ or — warfarin Concentrations of warfarin may be altered when co-administered with telaprevir. The international normalized ratio (INR) should be monitored when warfarin is co-administered with telaprevir.
ANTICONVULSANTS
carbamazepine
phenobarbital
phenytoin
↓ telaprevir
↑ carbamazepine
↑ or — phenytoin
↑ or — phenobarbital
Concentrations of the anticonvulsant may be altered and concentrations of telaprevir may be decreased. Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin.
Telaprevir may be less effective in patients taking these agents concomitantly.
Clinical or laboratory monitoring of carbamazepine, phenobarbital, and phenytoin concentrations and dose titration are recommended to achieve the desired clinical response.
ANTIDEPRESSANTS
escitalopram ↔ telaprevir
↓ escitalopram
Concentrations of escitalopram were decreased when co-administered with telaprevir. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with telaprevir.
trazodone ↑ trazodone Concomitant use of trazodone and telaprevir may increase plasma concentrations of trazodone which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone is used with telaprevir, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIFUNGALS
ketoconazole
itraconazole
posaconazole
voriconazole
↑ ketoconazole
↑ telaprevir

↑ itraconazole
↑ posaconazole
↑ or — voriconazole
Ketoconazole increases the plasma concentrations of telaprevir. Concomitant systemic use of itraconazole or posaconazole with telaprevir may increase plasma concentration of telaprevir.
Plasma concentrations of itraconazole, ketoconazole, or posaconazole may be increased in the presence of telaprevir. When co-administration is required, high doses of itraconazole or ketoconazole (greater than 200 mg/day) are not recommended.

Caution is warranted and clinical monitoring is recommended for itraconazole, posaconazole and voriconazole.

QT interval prolongation and Torsade de Pointes have been reported with voriconazole and posaconazole. QT interval prolongation has been reported with ketoconazole.
Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction with telaprevir. Voriconazole should not be administered to patients receiving telaprevir unless an assessment of the benefit/risk ratio justifies its use.
ANTI GOUT
colchicine ↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with telaprevir, due to the risk of colchicine toxicity. A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function.
Treatment of gout flares: co-administration of colchicine in patients on telaprevir:
0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.
If used for prophylaxis of gout flares: co-administration of colchicine in patients on telaprevir:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF): co-administration of colchicine in patients on telaprevir:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
rifabutin ↓ telaprevir
↑ rifabutin
Concentrations of telaprevir may be decreased, while rifabutin concentrations may be increased during co-administration. Telaprevir may be less effective due to decreased concentrations. The concomitant use of rifabutin and telaprevir is not recommended.
BENZODIAZEPINES
alprazolam
↑ alprazolam
Concomitant use of alprazolam and telaprevir increases exposure to alprazolam. Clinical monitoring is warranted.
parenterally
administered
midazolam



↑ midazolam


Concomitant use of parenterally administered midazolam with telaprevir increased exposure to midazolam. Co-administration should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.
Dose reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Co-administration of oral midazolam with telaprevir is contraindicated.
zolpidem (non-benzodiazepine sedative) ↓ zolpidem Exposure to zolpidem was decreased when co-administered with telaprevir. Clinical monitoring and dose titration of zolpidem is recommended to achieve the desired clinical response.
CALCIUM CHANNEL BLOCKERS
amlodipine ↑amlodipine
Exposure to amlodipine was increased when co-administered with telaprevir. Caution should be used and dose reduction for amlodipine should be considered. Clinical monitoring is recommended.
diltiazem
felodipine
nicardipine
nifedipine
nisoldipine
verapamil
↑calcium channel blockers Concentrations of other calcium channel blockers may be increased when telaprevir is co-administered.
Caution is warranted and clinical monitoring of patients is recommended.
CORTICOSTEROIDS
Systemic
prednisone
methylprednisolone
↑ prednisone
↑ methylprednisolone
Systemic corticosteroids such as prednisone and methylprednisolone are CYP3A substrates. Since telaprevir is a potent CYP3A inhibitor, plasma concentrations of these corticosteroids can be increased significantly. Co-administration of systemic corticosteroids and telaprevir is not recommended [see Warnings and Precautions ].
Systemic
dexamethasone
↓ telaprevir
Systemic dexamethasone induces CYP3A and can thereby decrease telaprevir plasma concentrations. This may result in loss of therapeutic effect of telaprevir. Therefore this combination should be used with caution or alternatives should be considered.
Inhaled/Nasal
fluticasone
budesonide
↑ fluticasone
↑ budesonide
Concomitant use of inhaled fluticasone or budesonide and telaprevir may increase plasma concentrations of fluticasone or budesonide resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone or budesonide and telaprevir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
ENDOTHELIN RECEPTOR ANTAGONIST
bosentan ↑ bosentan Concentrations of bosentan may be increased when co-administered with telaprevir. Caution is warranted and clinical monitoring is recommended.
HIV-ANTIVIRAL AGENTS: HIV-PROTEASE INHIBITORS (PIs)
atazanavir/ritonavir ↓ telaprevir
↑ atazanavir
Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.
darunavir/ritonavir ↓ telaprevir
↓ darunavir
Concomitant administration of telaprevir and darunavir/ritonavir resulted in reduced steady-state exposures to telaprevir and darunavir. It is not recommended to co-administer darunavir/ritonavir and telaprevir.
fosamprenavir/ritonavir ↓ telaprevir
↓ fosamprenavir
Concomitant administration of telaprevir and fosamprenavir/ritonavir resulted in reduced steady-state exposures to telaprevir and amprenavir. It is not recommended to co-administer fosamprenavir/ritonavir and telaprevir.
lopinavir/ritonavir ↓ telaprevir
↔ lopinavir
Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced steady-state telaprevir exposure, while the steady-state exposure to lopinavir was not affected. It is not recommended to co-administer lopinavir/ritonavir and telaprevir.
HIV-ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
efavirenz ↓ telaprevir
↓ efavirenz
Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.
tenofovir disoproxil fumarate ↔ telaprevir
↑ tenofovir
Concomitant administration of telaprevir and tenofovir disoproxil fumarate resulted in increased tenofovir exposure. Increased clinical and laboratory monitoring are warranted. Tenofovir disoproxil fumarate should be discontinued in patients who develop tenofovir-associated toxicities.
HMG-CoA REDUCTASE INHIBITORS
atorvastatin ↑ atorvastatin Plasma concentrations of atorvastatin are markedly increased when co-administered with telaprevir. Avoid concomitant administration of telaprevir and atorvastatin.
HORMONAL CONTRACEPTIVES/ESTROGEN
ethinyl estradiol
norethindrone
↓ ethinyl estradiol
↔ norethindrone
Exposure to ethinyl estradiol was decreased when co-administered with telaprevir. Two effective non-hormonal methods of contraception should be used during treatment with telaprevir.
Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Refer also to Contraindications (4) , Warnings and Precautions , Use in Specific Populations , and Patient Counseling Information .
IMMUNOSUPPRESSANTS
cyclosporine
sirolimus
tacrolimus
↑ cyclosporine
↑ sirolimus
↑ tacrolimus
Plasma concentrations of cyclosporine and tacrolimus are markedly increased when co-administered with telaprevir. Plasma concentration of sirolimus may be increased when co-administered with telaprevir, though this has not been studied. Significant dose reductions and prolongation of the dosing interval of the immunosuppressant to achieve the desired blood levels should be anticipated. Close monitoring of the immunosuppressant blood levels, and frequent assessments of renal function and immunosuppressant-related side effects are recommended when co-administered with telaprevir. Tacrolimus may prolong the QT interval. The use of telaprevir in organ transplant patients has not been studied.
INHALED BETA AGONIST
salmeterol ↑ salmeterol Concentrations of salmeterol may be increased when co-administered with telaprevir. Concurrent administration of salmeterol and telaprevir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NARCOTIC ANALGESIC
methadone ↓ R-methadone
Concentrations of methadone were reduced when co-administered with telaprevir. No adjustment of methadone dose is required when initiating co-administration of telaprevir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients.
PDE5 INHIBITORS
sildenafil
tadalafil
vardenafil
↑ PDE5 inhibitors Concentrations of PDE5 inhibitors may be increased when co-administered with telaprevir. For the treatment of erectile dysfunction, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE5 inhibitor-associated adverse events.
QT interval prolongation has been reported with vardenafil. Caution is warranted and clinical monitoring is recommended.
Co-administration of sildenafil or tadalafil and telaprevir in the treatment of pulmonary arterial hypertension is contraindicated [see Contraindications (4) ].

1 These interactions have been studied. See Clinical Pharmacology, Tables 6 and 7.

In addition to the drugs included in Table 5, the interaction between INCIVEK and the following drug was evaluated in clinical trials and no dose adjustment is needed for either drug [see Clinical Pharmacology ]: esomeprazole, raltegravir, or buprenorphine.

OVERDOSAGE

The highest documented dose administered is 1875 mg every 8 hours for 4 days in healthy subjects with INCIVEK alone. In that trial, the following common adverse events were reported more frequently with the 1875 mg q8h regimen compared to the 750 mg q8h regimen: nausea, headache, diarrhea, decreased appetite, dysgeusia, and vomiting.

No specific antidote is available for overdose with INCIVEK. Treatment of overdose with INCIVEK consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. In the event of an overdose, it is reasonable to employ the standard supportive measures, such as, removing unabsorbed material from the gastrointestinal tract, employing clinical monitoring (including obtaining an electrocardiogram), and instituting supportive therapy if required.

It is not known whether telaprevir is dialyzable by peritoneal or hemodialysis.

CONTRAINDICATIONS

Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment.

INCIVEK combination treatment is contraindicated in:

  • women who are or may become pregnant. Ribavirin may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug treatment, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions, Use in Specific Populations, and Patient Counseling Information ].
  • men whose female partners are pregnant.

INCIVEK is contraindicated when combined with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). INCIVEK is contraindicated when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of INCIVEK. Contraindicated drugs are listed below in Table 3 [also see Drug Interactions (7), Table 5 and Clinical Pharmacology, Tables 6 and 7 ].

Table 3: Drugs that are Contraindicated with INCIVEK
Drug Class Drugs within Class that are Contraindicated with INCIVEK Clinical Comments
Alpha 1-adrenoreceptor antagonist Alfuzosin Potential for hypotension or cardiac arrhythmia
Antimycobacterials Rifampin Rifampin significantly reduces telaprevir plasma concentrations.
Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Potential for acute ergot toxicity characterized by peripheral vasospasm or ischemia
GI motility agent Cisapride Potential for cardiac arrhythmias
Herbal products St. John's wort (Hypericum perforatum) Plasma concentrations of telaprevir can be reduced by concomitant use of the herbal preparation St. John's wort.
HMG CoA reductase inhibitors Lovastatin, simvastatin Potential for myopathy including rhabdomyolysis
Neuroleptic Pimozide Potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias
PDE5 inhibitor Sildenafil (Revatio®) or tadalafil (Adcirca®) [for treatment of pulmonary arterial hypertension] 1 Potential for PDE5 inhibitor-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope
Sedatives/hypnotics Orally administered midazolam 2, triazolam Prolonged or increased sedation or respiratory depression

1 See Drug Interactions, Table 5 for co-administration of sildenafil and tadalafil when dosed for erectile dysfunction.
2 See Drug Interactions, Table 5 for parenterally administered midazolam.

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017