telaprevir
Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
Indications and Usage for Incivek
Chronic Hepatitis C
Incivek™ (telaprevir), in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment-naïve or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers [see Clinical Studies (14.2 and 14.3), including definitions of these terms].
The following points should be considered when initiating treatment with Incivek:
- Incivek must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin [see Warnings and Precautions (5.7)].
- A high proportion of previous null responders (particularly those with cirrhosis) did not achieve a Sustained Virologic Response (SVR) and had telaprevir resistance-associated substitutions emerge on treatment with Incivek combination treatment [see Microbiology (12.4) and Clinical Studies (14.3)].
- Incivek efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes Incivek or other HCV NS3/4A protease inhibitors [see Microbiology (12.4)].
Incivek Dosage and Administration
Incivek/Peginterferon Alfa/Ribavirin Combination Treatment
The recommended dose of Incivek tablets is 750 mg (two 375-mg tablets) taken orally 3 times a day (7-9 hours apart) with food (not low fat) [see Clinical Pharmacology (12.3) and Patient Counseling Information (17.4)].
For specific dosage instructions for peginterferon alfa and ribavirin, refer to their respective prescribing information.
Duration of Treatment
The recommended duration of treatment with Incivek is 12 weeks in combination with peginterferon alfa and ribavirin. HCV-RNA levels should be monitored at weeks 4 and 12 to determine combination treatment duration and assess for treatment futility (Tables 1 and 2).
| |||
| Treatment-Naïve and Prior Relapse Patients | |||
| HCV-RNA* | Triple Therapy Incivek, peginterferon alfa and ribavirin | Dual Therapy peginterferon alfa and ribavirin | Total Treatment Duration |
| Undetectable at Weeks 4 and 12 | First 12 weeks | Additional 12 weeks | 24 weeks |
| Detectable (1000 IU/mL or less) at Weeks 4 and/or 12 | First 12 weeks | Additional 36 weeks | 48 weeks |
| Prior Partial and Null Responder Patients | |||
| Triple Therapy Incivek, peginterferon alfa and ribavirin | Dual Therapy peginterferon alfa and ribavirin | Total Treatment Duration | |
| All Patients | First 12 weeks | Additional 36 weeks | 48 weeks |
For the purpose of assessing response-guided therapy eligibility at weeks 4 and 12 (see Table 1), an "undetectable" HCV-RNA result is required; a confirmed "detectable but below limit of quantification" HCV-RNA result should not be considered equivalent to an "undetectable" HCV-RNA result [see Laboratory Tests (5.6)].
Treatment-naïve patients with cirrhosis who have undetectable HCV-RNA at weeks 4 and 12 of Incivek combination treatment may benefit from an additional 36 weeks of peginterferon alfa and ribavirin (48 weeks total) [see Clinical Studies (14.2)].
Dose Reduction
To prevent treatment failure, the dose of Incivek must not be reduced or interrupted. Refer to the respective prescribing information for dose modification of peginterferon alfa and ribavirin [see Warnings and Precautions (5.7)].
Discontinuation of Dosing
Patients with inadequate viral response are unlikely to achieve SVR, and may develop treatment-emergent resistance substitutions [see Microbiology (12.4)]. Discontinuation of therapy is recommended in all patients with (1) HCV-RNA levels of greater than or equal to 1000 IU/mL at Treatment Week 4 or 12; or (2) confirmed detectable HCV-RNA levels at Treatment Week 24 (see Table 2).
| HCV-RNA | Action |
|---|---|
| Week 4 or Week 12: Greater than 1000 IU/mL | Discontinue Incivek and peginterferon alfa and ribavirin (Incivek treatment complete at 12 weeks) |
| Week 24: Detectable | Discontinue peginterferon alfa and ribavirin |
If peginterferon alfa or ribavirin is discontinued for any reason, Incivek must also be discontinued.
Dosage Forms and Strengths
Each tablet contains 375 mg of telaprevir. Tablets are available as purple, film-coated, capsule-shaped tablets debossed with the characters "V 375" on one side.
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 (5.1), Use in Specific Populations (8.1), and Patient Counseling Information (17.1)].
- 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 (12.3), Tables 6 and 7].
| 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 | Atorvastatin, lovastatin, simvastatin | Potential for myopathy including rhabdomyolysis |
| Neuroleptic | Pimozide | Potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics |
| PDE5 inhibitor | Sildenafil (Revatio®) or tadalafil (Adcirca®) [for treatment of pulmonary arterial hypertension]* | Potential for PDE5 inhibitor-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope |
| Sedatives/hypnotics | Orally administered midazolam†, triazolam | Prolonged or increased sedation or respiratory depression |
Warnings and Precautions
Pregnancy: Use with Ribavirin and Peginterferon Alfa
Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.
Because Incivek must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those drugs are applicable to combination therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use 2 effective contraceptive methods during treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests during treatment and during the 6-month period after stopping treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients as significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin [see Contraindications (4), Use in Specific Populations (8.1), and Patient Counseling Information (17.1)]. Refer also to the prescribing information for ribavirin.
Female Patients
Hormonal contraceptives may be continued but may not be reliable during Incivek dosing and for up to two weeks following cessation of Incivek [see Drug Interactions (7)]. During this time, female patients of childbearing potential should use two effective non-hormonal methods of contraception. Examples may include barrier methods or intrauterine devices (IUDs) [see also Use in Specific Populations: Pregnancy (8.1) and Patient Counseling Information (17.1)]. Two weeks after completion of Incivek treatment, hormonal contraceptives are again appropriate as one of the two required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives.
Serious Skin Reactions
Serious skin reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome (SJS) were reported in less than 1% of subjects who received Incivek combination treatment compared to none who received peginterferon alfa and ribavirin alone. These serious skin reactions required hospitalization, and all patients recovered. The presenting signs of DRESS may include rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips).
If a serious skin reaction occurs, all components of Incivek combination treatment must be discontinued immediately and the patient should be promptly referred for urgent medical care.
Rash
Rash developed in 56% of subjects who received Incivek combination treatment [see Adverse Reactions (6.1)]. Severe rash (e.g., a generalized rash or rash with vesicles or bullae or ulcerations other than SJS) was reported in 4% of subjects who received Incivek combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a prominent eczematous component.
Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe or if systemic symptoms develop, Incivek should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of Incivek discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered. Patients should be monitored until the rash has resolved. Incivek must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended [see Drug Interactions (7)].
Anemia
Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of Incivek to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. Hemoglobin values less than or equal to 10 g/dL were observed in 36% of subjects who received Incivek combination treatment compared to 17% of subjects who received peginterferon alfa and ribavirin. Hemoglobin values less than 8.5 g/dL were observed in 14% of subjects who received Incivek combination treatment compared to 5% of subjects receiving peginterferon alfa and ribavirin.
In subjects receiving Incivek combination treatment, 4% discontinued Incivek, 1% discontinued Incivek combination treatment, and 32% underwent a ribavirin dose modification (reduction, interruption or discontinuation) due to anemia. In subjects treated with peginterferon alfa and ribavirin alone, there were two discontinuations and 12% underwent ribavirin dose modification due to anemia.
Hemoglobin should be monitored prior to and at least every 4 weeks during Incivek combination treatment. For the management of anemia, ribavirin dose reductions should be used (refer to the prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose reductions are inadequate, discontinuation of Incivek should be considered. If ribavirin is permanently discontinued for the management of anemia, Incivek must also be permanently discontinued. Ribavirin may be restarted per the dosing modification guidelines for ribavirin. The dose of Incivek must not be reduced and Incivek must not be restarted if discontinued.
Drug Interactions
See Table 3 for a listing of drugs that are contraindicated for use with Incivek due to potentially life-threatening adverse events or potential loss of therapeutic effect to Incivek [see Contraindications (4)]. Refer to Table 5 for established and other potentially significant drug-drug interactions [see Drug Interactions (7)].
Laboratory Tests
HCV-RNA levels should be monitored at weeks 4 and 12 and as clinically indicated. Use of a sensitive real-time RT-PCR assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification equal to or less than 25 IU/mL and a limit of HCV-RNA detection of approximately 10-15 IU/mL. For the purpose of assessing response-guided therapy eligibility, an "undetectable" HCV-RNA result is required; a confirmed "detectable but below limit of quantification" HCV-RNA result should not be considered equivalent to an "undetectable" HCV-RNA result.
Hematology evaluations (including white cell differential count) are recommended at weeks 2, 4, 8 and 12 or as clinically appropriate thereafter.
Chemistry evaluations (electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, and TSH) are recommended as frequently as the hematology evaluations or as clinically indicated [see Adverse Reactions (6)].
Refer to the prescribing information for peginterferon alfa and ribavirin, including pregnancy testing requirements.
General
Incivek must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. Therefore, the prescribing information for peginterferon alfa and ribavirin must be consulted before starting treatment with Incivek.
There are no clinical data on re-treating patients who have failed an HCV NS3/4A protease inhibitor-based treatment, nor are there data on repeated courses of Incivek [see Microbiology (12.4)].
Hepatic Impairment
Incivek is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) or patients with decompensated liver disease. Refer to prescribing information for peginterferon alfa and ribavirin which must be co-administered with Incivek [see Use in Specific Populations: Hepatic Impairment (8.6)].
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the label:
- Pregnancy: Use with Ribavirin and Peginterferon alfa [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1), and Patient Counseling Information (17.1)]
- Serious Skin Reactions/Rash [see Warnings and Precautions (5.2 and 5.3)]
- Anemia [see Warnings and Precautions (5.4)]
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 (5.2, 5.3, and 5.4)]. 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 Incivek-treated subjects with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone (Table 4).
| Incivek, peginterferon alfa, and ribavirin Combination Treatment N=1797 | Peginterferon alfa and ribavirin N=493 | |
|---|---|---|
| ||
| Rash* | 56% | 34% |
| Fatigue | 56% | 50% |
| Pruritus | 47% | 28% |
| Nausea | 39% | 28% |
| Anemia* | 36% | 17% |
| Diarrhea | 26% | 17% |
| Vomiting | 13% | 8% |
| Hemorrhoids | 12% | 3% |
| Anorectal discomfort | 11% | 3% |
| Dysgeusia | 10% | 3% |
| Anal pruritus | 6% | 1% |
Description of Selected Adverse Drug Reactions
Rash
In controlled clinical trials, rash events (all grades) were reported in 56% of subjects who received Incivek combination treatment and in 34% of subjects who received peginterferon alfa and ribavirin. Rash most frequently began during the first 4 weeks, but could occur at any time during Incivek combination treatment. Improvement of rash occurs after Incivek dosing completion or discontinuation; however, rashes may take weeks for complete resolution.
Rash events led to discontinuation of Incivek alone in 6% of subjects and discontinuation of Incivek combination treatment in 1% of subjects.
For serious skin reactions and severe rash, see Warnings and Precautions (5.2 and 5.3).
Anemia
In controlled clinical trials, the overall incidence and severity of anemia increased with Incivek combination treatment compared to peginterferon alfa and ribavirin alone. The incidence of anemia adverse events was 36% with Incivek combination treatment compared to 17% with peginterferon alfa and ribavirin alone. A decrease in hemoglobin levels occurred during the first 4 weeks of treatment, with lowest values reached at the end of Incivek dosing. Hemoglobin values gradually returned to levels observed with peginterferon alfa and ribavirin after Incivek dosing was completed [see Warnings and Precautions (5.4)].
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.
Laboratory abnormalities
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 Incivek-treated subjects 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 Incivek-treated subjects 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 × 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/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.
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 studies (indicated with *) or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.
| 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* | ↑ 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. |
| desipramine trazodone | ↑ desipramine ↑ trazodone | Concomitant use of trazodone or desipramine and telaprevir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with telaprevir, the combination should be used with caution and a lower dose of trazodone or desipramine 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 (5.3)]. |
| 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. |
| 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 (5.1), Use in Specific Populations (8.1), and Patient Counseling Information (17.1). |
| 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* | ||
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