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The following adverse reactions are discussed in greater detail in other sections of the label:
- Serious Skin Reactions/Rash [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Anemia [see WARNINGS AND PRECAUTIONS]
- Pregnancy: Use with Ribavirin and Peginterferon alfa [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use in Specific Populations]
INCIVEK must be administered with peginterferon alfa and ribavirin. Refer to their respective prescribing information for their associated adverse reactions.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety assessment is based on data from pooled adequate and well-controlled clinical trials including 1797 subjects who received INCIVEK combination treatment and 493 who received peginterferon alfa and ribavirin.
Serious adverse drug reactions occurred in 3% of subjects who received INCIVEK combination treatment compared to none of the subjects treated with peginterferon alfa and ribavirin. The most frequent serious adverse events in subjects treated with INCIVEK combination treatment were skin disorders (rash and/or pruritus) and anemia [see WARNINGS AND PRECAUTIONS]. Fourteen percent of subjects discontinued INCIVEK due to adverse drug reactions. Rash, anemia, fatigue, pruritus, nausea, and vomiting were the most frequent adverse drug reactions leading to discontinuation of INCIVEK.
INCIVEK was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactions that occurred in subjects treated with INCIVEK with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone (Table 4).
Table 4: Clinical Adverse Drug Reactions Reported with
at Least 5% Higher Frequency Among Subjects Receiving INCIVEK
|INCIVEK, peginterferon alfa, and ribavirin Combination Treatment
|Peginterferon alfa and ribavirin
|*Rash and anemia based on SSC (Special Search Category) grouped terms.|
Description of Selected Adverse Drug Reactions
Anorectal Signs and Symptoms
In the controlled clinical trials, 29% of subjects treated with INCIVEK combination treatment experienced anorectal adverse events, compared to 7% of those treated with peginterferon alfa and ribavirin alone. The majority of these events (e.g., hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate in severity; less than 1% led to treatment discontinuation and all resolved during or after completion of INCIVEK dosing.
White Blood Cells: Treatment with peginterferon alfa is associated with decreases in mean values for total white blood cell, absolute neutrophil, and absolute lymphocyte count. More subjects treated with INCIVEK had decreases in lymphocyte counts to 499/mm³ or less (15% compared to 5%). Decreases in total white cell counts to 1,499/mm³ or less were comparable (8% compared to 5%). The incidence of decreases in absolute neutrophil counts to 749/mm³ or less was 15% in subjects treated with peginterferon alfa and ribavirin alone compared to 12% among those treated with INCIVEK combination treatment.
Platelets: Treatment with peginterferon alfa is associated with decreases in mean platelet counts. More patients treated with INCIVEK combination treatment had decreases in mean platelet values of all grades: 47% compared to 36% treated with peginterferon alfa and ribavirin alone. Three percent of INCIVEK combination treatment subjects had decreases to 49,999/mm³ or less compared to 1% of those treated with peginterferon alfa and ribavirin-treated alone.
Bilirubin: Forty one percent of subjects treated with INCIVEK compared to 28% of peginterferon alfa and ribavirin-treated subjects had all grade elevations in bilirubin levels; 4% and 2% of subjects, respectively, had greater than or equal to 2.6 x ULN elevations. Bilirubin levels increased most steeply during the first 1 to 2 weeks of INCIVEK dosing, stabilized and between Weeks 12 and 16 were at baseline levels.
Uric Acid: During the INCIVEK combination treatment period, 73% of subjects had elevated uric acid levels compared to 29% for those treated with peginterferon alfa and ribavirin alone. Shifts to greater than or equal to 12.1 mg per dL from baseline in uric acid levels were also more frequent among subjects treated with INCIVEK (7%) compared to peginterferon alfa and ribavirin (1%). Less than 1% of subjects had clinical events of gout/gouty arthritis; none were serious and none resulted in treatment discontinuation.
Additional Data from Clinical Trials
In the analysis of an additional study (Trial C211), the safety profile of combination treatment with INCIVEK 1125 mg twice daily was similar to the safety profile for patients receiving combination treatment with INCIVEK 750 mg every 8 hours (q8h) [see Clinical Studies]. No new safety findings were identified.
The following adverse reactions have been identified during post-approval use of INCIVEK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Renal and Urinary Disorders: Pre-renal azotemia with or without acute renal insufficiency/failure, uric acid nephropathy
Read the Incivek (telaprevir film-coated tablets) Side Effects Center for a complete guide to possible side effects
Potential for INCIVEK to Affect Other Drugs
INCIVEK is a strong 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 adverse reactions (see Table 5). INCIVEK is also an inhibitor of P-gp, OATP1B1, and OATP2B1. Co-administration of INCIVEK with drugs that are substrates for P-gp, OATP1B1, and OATP2B1 transport may result in increased plasma concentrations of such drugs, which could increase 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 on 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. Most drug interaction studies have been performed with a dose of 750 mg q8h of INCIVEK. The 1125 mg twice-daily regimen provides similar total daily exposures of telaprevir; thus drug interactions are expected to be similar between the two regimens when evaluated after multiple doses [see CLINICAL PHARMACOLOGY].
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|
|Careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when telaprevir is co-administered with alfentanil or fentanyl, including extended-release transdermal or transmucosal preparations of fentanyl.|
|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 coadministered with telaprevir.|
|digoxin*||↑ 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.|
|clarithromycin erythromycin telithromycin||↑ telaprevir
|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.|
|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.|
|escitalopram* trazodone||↔ telaprevir
|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.
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.
|ketoconazole* itraconazole posaconazole voriconazole||↑ ketoconazole
↑ 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.
|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).
|rifabutin||↓ telaprevir ↑ rifabutin||Concentrations of telaprevir may be decreased, while rifabutin concentrations may be increased during coadministration. Telaprevir may be less effective due to decreased concentrations. The concomitant use of rifabutin and telaprevir is not recommended.|
|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 (nonbenzodiazepine 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* diltiazem felodipine nicardipine nifedipine nisoldipine verapamil||↑amlodipine
↑calcium channel blockers
|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.
Concentrations of other calcium channel blockers may be increased when telaprevir is co-administered. Caution is warranted and clinical monitoring of patients is recommended.
|Systemic prednisone methylprednisolone||↑prednisone
|Systemic corticosteroids such as prednisone and methylprednisolone are CYP3A substrates. Since telaprevir is a strong 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
|Concomitant use of inhaled fluticasone or budesonide and telaprevir may increase plasma concentrations of fluticasone or budesonide resulting in significantly reduced serum cortisol concentrations. Coadministration 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)|
|Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased.|
|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.|
|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.|
|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 coadminister lopinavir/ritonavir and telaprevir.|
|HIV-ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS|
|Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.|
|tenofovir disoproxil fumarate*||↔ telaprevir
|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* fluvastatin pitavastatin pravastatin rosuvastatin||↑statin||Plasma concentrations of atorvastatin are markedly increased when co-administered with telaprevir. Avoid concomitant administration of telaprevir and atorvastatin. For fluvastatin, pitavastatin, pravastatin, and rosuvastatin, caution is warranted and clinical monitoring is recommended. Refer to CONTRAINDICATIONS for HMG-CoA reductase inhibitors (lovastatin, simvastatin) that are contraindicated with INCIVEK.|
|ethinyl estradiol* norethindrone||↓ethinyl estradiol
|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, WARNINGS AND PRECAUTIONS, and Use In Specific Populations.|
|cyclosporine* sirolimus tacrolimus*||↑ cyclosporine
|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.|
|repaglinide||↑ repaglinide||Caution is warranted and clinical monitoring is recommended.|
|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.|
|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].
|*These interactions have been studied. See CLINICAL PHARMACOLOGY, Tables 6 and 7. The direction of the arrow (↑ = increase, ↓ = decrease, ⇔ = no change) indicates the direction of the change in PK.|
In addition to the drugs included in Table 5, the interaction between INCIVEK and the following drugs was evaluated in clinical trials and no dose adjustment is needed for any drug [see CLINICAL PHARMACOLOGY]: esomeprazole, raltegravir, or buprenorphine.
Read the Incivek Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/8/2013
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