Viekirax (Ombitasvir, Paritaprevir, and Ritonavir)

Viekirax is a fixed-dose combination of three antiviral drugs Ombitasvir, paritaprevir, and ritonavir indicated for the treatment of chronic hepatitis C (genotype 4) in combination with ribavirin.

Viekirax (Ombitasvir, paritaprevir, and ritonavir) Uses:

Chronic hepatitis C:
- Without cirrhosis, treatment of chronic hepatitis C virus (HCV) genotype 4 infection or with compensated cirrhosis, in combination with ribavirin.

Viekirax (Ombitasvir, paritaprevir, and ritonavir) Dose in Adults

Viekirax (Ombitasvir, paritaprevir, and ritonavir) Dose in the treatment of chronic hepatitis C, genotype 4 infection:

Treatment-naive or peginterferon/ ribavirin-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh class A]) (alternative regimen):

P/O:
- In combination with ribavirin, 2 tablets once daily (every morning) for 12 weeks.

Use in Children:

the efficacy and safety of the drugs have not been established in pediatric patients.

Pregnancy Risk Category: B

Hepatitis C treatment is not recommended for pregnant women or to reduce the chance of mother-to child transmission.
To reduce the risk of HCV transmission, HCV-infected women with childbearing potential may want to postpone pregnancy until treatment is completed.
If HCV infection is discovered during pregnancy, treatment should be delayed until after delivery.
Direct-acting antiviral medication should not be administered to pregnant women unless safety and efficacy data are available.
Contraindicated is concurrent use of Ethinyl estradiol-containing contraceptives.
Alternative methods of contraception, such as progestin-only contraception or nonhormonal methods, are suggested during therapy.
If ribavirin is used together with it, all warnings regarding pregnancy and contraception must be observed.
Refer to the ribavirin monograph for additional information.

Use during breastfeeding:

Ritonavir can be found in breast milk (refer the ritonavir monograph for more information).
It is unknown if breast milk contains ombitasvir and paritaprevir.
When deciding whether to discontinue or continue breastfeeding during therapy, it is important to consider the risks to infants, the benefits to the mother, and the benefits to the mother.
The spread of the hepatitis C viruses is not linked to breastfeeding.
Breastfeeding is not recommended if the nipples are cracked, bleeding or swollen.
Breastfeeding is not recommended in the case of HIV co-infection.

Viekirax (Ombitasvir, paritaprevir, and ritonavir) Dose in Kidney Disease:

CrCl ≥15 mL/minute:
- No dosage adjustment is necessary.
End-stage renal disease (ESRD) on dialysis:
- In the manufacturer's labeling, there are no dosage adjustments provided. (has not been studied).

Viekirax (Ombitasvir, paritaprevir, and ritonavir) Dose in Liver Disease:

Hepatic impairment prior to treatment initiation:
- Mild impairment (Child-Pugh class A):
  - No dosage adjustment is necessary.
- Moderate or severe impairment (Child-Pugh class B or C):
  - Use is contraindicated.
Hepatotoxicity during treatment:
- ALT >10 times ULN (persistent):
  - Consider therapy discontinuation.
- ALT increased along with signs or symptoms of hepatic inflammation, increasing direct bilirubin, alkaline phosphatase, or INR:
  - Discontinue therapy.
- Evidence of hepatic decompensation:
  - Discontinue therapy

Side Effects of Viekirax (Ombitasvir, paritaprevir, and ritonavir):

Neuromuscular & skeletal:
- Asthenia

Central Nervous System:
- Fatigue
- Insomnia
Dermatologic:
- Allergic Skin Reaction
- Pruritus
Gastrointestinal:
- Nausea

Hematologic & Oncologic:
- Anemia
- Decreased Hemoglobin
Hepatic:
- Increased Serum Alanine Aminotransferase

Contraindications to Viekirax (Ombitasvir, paritaprevir, and ritonavir):

Hypersensitivity to ritonavir (eg toxic epidermal nécrolysis, Stevens Johnson syndrome, or any component)
Moderate to severe liver impairment (Child Puugh class B orC).
Concurrent use drugs that are dependent on CYP3A to clear is linked with serious and life-threatening complications.
Use of strong or moderate inducers of CYP3A in conjunction

Concurrent use drugs that are contraindicated includes, but is not limited to:

Alfuzosin and atorvastatin are used in patients with renal or hepatic impairment.

Notice:

There are also contraindications to Ribavirin.
See prescribing information for ribavirin.

Canadian labeling:Additional contraindications not listed in the US labeling:

Concurrent use of avasimibe (not accessible in Canada), nufcillin, fusidic acid oral (not available to Canada), astemizole and disopyramide.
Pregnant women
Female partners who are pregnant by a male partner could be pregnant or planning to become pregnant.

Warnings and precautions

Hepatic effects
- Paritaprevir, ombitasvir and ritonavir have been associated with hepatic decompensation, hepatic failure, liver transplantation, and fatal cases.
- Most patients had signs of cirrhosis before treatment began.
- It usually takes between one and four weeks for the treatment to begin.
- Acute elevation of direct bilirubin, without ALT elevation, and other signs and symptoms that may indicate hepatic decompensation.
- Before starting treatment, evaluate your liver function, including direct bilirubin, within the first four weeks. Continue treatment as indicated.
- Patients with compensated liver disease should be examined for signs and symptoms of hepatic dysfunction (eg ascites, hepatic neuropathy, variceal hemorhage).
- Stop treating patients with signs or symptoms of hepatic impairment.
Elevation of hepatic enzymes
- Reports have indicated that ALT levels were higher than ULN by at least 5 times.
- Elevations usually occur within four weeks of treatment initiation. They are often asymptomatic and disappear within 2-8 weeks of continued dosing.
- Examine the liver enzymes for clinical indications during the first four weeks.
- If ALT is high, repeat the testing and monitor closely.
- Patients should immediately inform their doctor if they experience fatigue, weakness, vomiting, nausea, jaundice, discolored feces, or any other symptoms.
- Consider discontinuing ALT if it persists at >10x ULN.
- If ALT increases are accompanied by signs or inflammation of the liver, discontinue using it.
- Women who use Ethinyl estradiol products may be at greater risk
- For concomitant use of estrogen products, refer to Special Populations.
Diabetes:
- Patients with diabetes may experience a rapid decrease in hepatitis C virus load after direct-acting antiviral therapy (DAA) for hepatitis C.
- This could lead to an improvement of glucose metabolism and possibly symptomatic hypoglycemia if the antidiabetic drugs are continued at the same dosage.
- DAA therapy is a 3 month-long treatment that examines for changes in glucose tolerance. Patients are also informed about the possibility of hypoglycemia.
- Modifications to anti-diabetic therapy can be significant.
Hepatic impairment
- In cases of moderate or severe hepatic impairment (Child Puugh class B, C), use is not recommended.
Hepatitis B virus activation: [US-Boxed Warning]
- Hepatitis B virus reactivation (HBV), has been reported in hepatitis C viral (HCV) co-infected patients receiving or having completed treatment with HCV direct acting antivirals but not receiving HBV antiviral treatment.
- Some cases can lead to fulminant liver disease, hepatic failure and even death.
- Before initiating treatment, all patients should be tested for evidence of HBV infection.
- During treatment, and after-treatment follow up, monitor HCV/HBV coinfected patients for flare-ups or reactivation of HBV.
- As soon as HBV infection is diagnosed, initiate treatment.
- HBV reactivation was reported in HBsAg-positive patients and patients with serologic evidence that resolved HBV infection (i.e. HBsAg Negative and Anti-HBc Positive) and is characterized as an abrupt increase of HBV replication manifested by a rapid rise in serum HBV DNA levels.
- Patients with a resolved HBV infection may experience HBsAg recurrence.
- Patients who are taking immunosuppressants and chemotherapeutic drugs may have a higher risk of HBV reactivation.

Ombitasvir, paritaprevir, and ritonavir: Drug Interaction

Risk Factor C (Monitor therapy)
Alosetron	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron.
ALPRAZolam	Ombitasvir, Paritaprevir, and Ritonavir may increase the serum concentration of ALPRAZolam.
Amiodarone	Ombitasvir, Paritaprevir, and Ritonavir may increase the serum concentration of Amiodarone.
Antidiabetic Agents	Direct Acting Antiviral Agents (HCV) may enhance the hypoglycemic effect of Antidiabetic Agents.
Benperidol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benperidol.
Benzhydrocodone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased.
Bepridil	Antihepaciviral Combination Products may increase the serum concentration of Bepridil.
Betamethasone (Ophthalmic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Ophthalmic).
Bictegravir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bictegravir.
Bortezomib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib.
Brentuximab Vedotin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.
Brentuximab Vedotin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.
Brinzolamide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide.
Budesonide (Nasal)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal).
Budesonide (Oral Inhalation)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation).
Buprenorphine	Ombitasvir, Paritaprevir, and Ritonavir may increase the serum concentration of Buprenorphine.
BuPROPion	Antihepaciviral Combination Products may decrease the serum concentration of BuPROPion.
Calcifediol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol.
Cannabidiol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabidiol.
Cannabis	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased.
Carisoprodol	Ombitasvir, Paritaprevir, and Ritonavir may decrease the serum concentration of Carisoprodol.
Celiprolol	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol.
Cinacalcet	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cinacalcet.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CloZAPine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
CloZAPine	CYP1A2 Inducers may decrease the serum concentration of CloZAPine.
Codeine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Codeine.
Corticosteroids (Orally Inhaled)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic).
Corticosteroids (Systemic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE.
Cyclobenzaprine	Ombitasvir, Paritaprevir, and Ritonavir may decrease the serum concentration of Cyclobenzaprine.
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Darolutamide	Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Darolutamide.
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Dexamethasone (Ophthalmic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dexamethasone (Ophthalmic).
DiazePAM	Ombitasvir, Paritaprevir, and Ritonavir may decrease the serum concentration of DiazePAM.
Dienogest	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dienogest.
Dofetilide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dofetilide.
Doxercalciferol	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol.
Dronabinol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol.
Dutasteride	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride.
Estazolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estazolam.
Estrogen Derivatives	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estrogen Derivatives.
Evogliptin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Evogliptin.
Flecainide	Antihepaciviral Combination Products may increase the serum concentration of Flecainide. Management: Canadian labeling recommends avoiding this combination.
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fostamatinib	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fostamatinib.
Galantamine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Galantamine.
Gefitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib.
Ifosfamide	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide.
Imatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib.
Imidafenacin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin.
Lacosamide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide.
Levobupivacaine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
LinaGLIPtin	Antihepaciviral Combination Products may increase the serum concentration of LinaGLIPtin.
Lumefantrine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
MedroxyPROGESTERone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of MedroxyPROGESTERone.
MetFORMIN	Ombitasvir, Paritaprevir, and Ritonavir may enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased.
Mexiletine	Antihepaciviral Combination Products may increase the serum concentration of Mexiletine.
Mirtazapine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirtazapine.
Naldemedine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naldemedine.
Naldemedine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.
Nalfurafine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nalfurafine.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Nintedanib	Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib.
OLANZapine	Antihepaciviral Combination Products may decrease the serum concentration of OLANZapine.
Omeprazole	Antihepaciviral Combination Products may decrease the serum concentration of Omeprazole.
Ospemifene	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene.
Oxybutynin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin.
Parecoxib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib.
Paricalcitol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol.
P-glycoprotein/ABCB1 Substrates	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide.
Pimecrolimus	CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus.
Polatuzumab Vedotin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be increased.
Pranlukast	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast.
Praziquantel	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel.
PrednisoLONE (Systemic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of PrednisoLONE (Systemic).
PredniSONE	CYP3A4 Inhibitors (Strong) may increase the serum concentration of PredniSONE.
Proguanil	Antihepaciviral Combination Products may decrease the serum concentration of Proguanil.
Propafenone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Propafenone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Propafenone	Antihepaciviral Combination Products may increase the serum concentration of Propafenone. Management: Canadian labeling recommends avoiding this combination.
Prucalopride	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride.
QuiNIDine	Ombitasvir, Paritaprevir, and Ritonavir may increase the serum concentration of QuiNIDine. Management: Canadian labeling recommends avoiding this combination.
Ramelteon	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon.
Repaglinide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure.
Retapamulin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations.
RifAXIMin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin.
RomiDEPsin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Sibutramine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Sibutramine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sibutramine.
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
SORAfenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib.
Tacrolimus (Topical)	Ombitasvir, Paritaprevir, and Ritonavir may increase the serum concentration of Tacrolimus (Topical).
Talazoparib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs.
Talazoparib	BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib.
Tasimelteon	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon.
Tegaserod	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod.
Tetrahydrocannabinol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol.
Tetrahydrocannabinol and Cannabidiol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
TraMADol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol.
Triamcinolone (Systemic)	Antihepaciviral Combination Products may increase the serum concentration of Triamcinolone (Systemic).
Upadacitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Upadacitinib.
Vilanterol	May increase the serum concentration of CYP3A4 Inhibitors (Strong).
Vindesine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine.
Vinorelbine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine.
Warfarin	Ombitasvir, Paritaprevir, and Ritonavir may diminish the anticoagulant effect of Warfarin.
Risk Factor D (Consider therapy modification)
Abemaciclib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Abemaciclib. Management: In patients taking abemaciclib at a dose of 200 mg or 150 mg twice daily, reduce the dose to 100 mg twice daily when combined with strong CYP3A4 inhibitors. In patients taking abemaciclib 100 mg twice daily, decrease the dose to 50 mg twice daily.
Afatinib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. Iif used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib.
Alitretinoin (Systemic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor.
Almotriptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function.
Alpelisib	BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions.
AmLODIPine	Antihepaciviral Combination Products may increase the serum concentration of AmLODIPine. Management: Reduce amlodipine dose by at least 50% and monitor for increased amlodipine effects (eg, hypotension) if an antihepaciviral combination product is initiated.
Apixaban	Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Apixaban. Management: US labeling recommends a 50% apixaban dose reduction in patients who would otherwise receive 5 or 10 mg twice daily, and avoiding in patients who would otherwise receive 2.5 mg twice daily. Canadian labeling lists any combined use as contraindicated.
ARIPiprazole	CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details.
ARIPiprazole Lauroxil	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments.
Bedaquiline	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bedaquiline. Management: Limit duration of concurrent use of bedaquiline with CYP3A4 inhibitors to no more than 14 days, unless the benefit of continued use outweighs the possible risks. Monitor for toxic effects of bedaquiline. Exceptions discussed in separate monographs.
Betrixaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor.
Bilastine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors.
Brexpiprazole	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose 50% with strong CYP3A4 inhibitors; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer.
Brigatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with strong CYP3A4 inhibitors when possible. If combination cannot be avoided, reduce the brigatinib dose by approximately 50%, rounding to the nearest tablet strength (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg).
Budesonide (Topical)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased.
BusPIRone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of BusPIRone. Management: Limit the buspirone dose to 2.5 mg daily and monitor patients for increased buspirone effects/toxicities if combined with strong CYP3A4 inhibitors.
Cabazitaxel	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose.
Cabozantinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details.
Candesartan	Antihepaciviral Combination Products may increase the serum concentration of Candesartan. Management: Per antihepaciviral combination product US prescribing information, consider decreasing the candesartan dose and monitoring for evidence of hypotension and worsening renal function if these agents are used in combination.
Cariprazine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details.
Ceritinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Exceptions discussed in separate monographs.
Cilostazol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4.
Cladribine	BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration.
Clarithromycin	Antihepaciviral Combination Products may increase the serum concentration of Clarithromycin. Management: Avoid clarithromycin doses greater than 1000 mg/day when used with an antihepaciviral combination product. Further dose reductions may be needed in patients with impaired renal function. Consider an alternative antimicrobial for any non-MAC infection.
Copanlisib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Copanlisib. Management: If concomitant use of copanlisib and strong CYP3A4 inhibitors cannot be avoided, reduce the copanlisib dose to 45 mg. Monitor patients for increased copanlisib effects/toxicities.
Crizotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors whenever possible. If combined use cannot be avoided, decrease the crizotinib dose to 250 mg daily. Exceptions are discussed in separate monographs.
CycloSPORINE (Systemic)	Ombitasvir, Paritaprevir, and Ritonavir may increase the serum concentration of CycloSPORINE (Systemic). Management: Reduce cyclosporine dose by 80% when initiating therapy with ombitasvir/paritaprevir/ritonavir and monitor cyclosporine blood levels closely.
CYP3A4 Inhibitors (Strong)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Substrates (High risk with Inhibitors)	CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); AmLODIPine; Benzhydrocodone; Buprenorphine; Gefitinib; HYDROcodone; Mirtazapine; Praziquantel; Telithromycin; Vinorelbine.
Dabigatran Etexilate	P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling.
Daclatasvir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat.
Darunavir	Ombitasvir, Paritaprevir, and Ritonavir may decrease the serum concentration of Darunavir. Management: These agents can be combined in treatment naive patients or those with no darunavir resistance if the darunavir dose is 800 mg daily, darunavir is administered at the same time as the combination product, and darunavir is given without ritonavir.
Dasatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: This combination should be avoided if possible. If combined, dasatinib dose reductions are recommended. See full monograph for details. Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Deflazacort	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor.
Delamanid	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Delamanid. Management: Increase ECG monitoring frequency if delamanid is combined with strong CYP3A4 inhibitors due to the risk for QTc interval prolongation. Continue frequent ECG assessments throughout full delamanid treatment period. Exceptions discussed separately.
Digoxin	Ombitasvir, Paritaprevir, and Ritonavir may increase the serum concentration of Digoxin. Management: When initiating the ombitasvir/paritaprevir/ritonavir combination product in patients taking digoxin, decrease the digoxin dose by 30% to 50% and monitor serum digoxin levels to determine further dose adjustments.
DOCEtaxel	CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOCEtaxel. Management: Avoid the concomitant use of docetaxel and strong CYP3A4 inhibitors when possible. If combined use is unavoidable, consider a 50% docetaxel dose reduction and monitor for increased docetaxel toxicities.
DOXOrubicin (Conventional)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided.
DOXOrubicin (Conventional)	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided.
Drospirenone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Drospirenone. Management: Drospirenone use is contraindicated specifically when the strong CYP3A4 inhibitors atazanavir and cobicistat are administered concurrently. Caution should be used when drospirenone is coadministered with other strong CYP3A4 inhibitors.
Duvelisib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Duvelisib. Management: Reduce the dose of duvelisib to 15 mg twice a day when used together with a strong CYP3A4 inhibitor.
Edoxaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation.
Eliglustat	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details.
Eluxadoline	Antihepaciviral Combination Products may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with antihepaciviral combination products. Monitor patients for increased eluxadoline effects/toxicities.
Encorafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Encorafenib. Management: Avoid concomitant use of encorafenib and strong CYP3A4 inhibitors whenever possible. If concomitant administration is unavoidable, decrease the encorafenib dose. See monograph for details.
Entrectinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Entrectinib. Management: Avoid strong CYP3A4 inhibitors during treatment with entrectinib. Reduce dose to 100 mg/day if combination cannot be avoided in adults and those 12 yrs of age or older with a BSA of at least 1.5 square meters. No alternative dosing provided for others.
Erdafitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erdafitinib. Management: Avoid concomitant use of erdafitinib and strong CYP3A4 inhibitors when possible. If combined, monitor closely for erdafitinib adverse reactions and consider dose modifications accordingly.
Erlotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements).
Eszopiclone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression).
Etizolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely.
Fedratinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fedratinib. Management: Consider alternatives when possible. If used together, decrease fedratinib dose to 200 mg/day. After the inhibitor is stopped, increase fedratinib to 300 mg/day for the first 2 weeks and then to 400 mg/day as tolerated.
FentaNYL	CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary.
Fesoterodine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors.
Fluticasone (Oral Inhalation)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely.
Gilteritinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gilteritinib. Management: Consider alternatives to the use of a strong CYP3A4 inhibitor with gilteritinib. If the combination cannot be avoided, monitor more closely for evidence of gilteritinib toxicities.
Glasdegib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Glasdegib. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor closely for evidence of QT interval prolongation and other adverse reactions to glasdegib.
GuanFACINE	CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination.
HYDROcodone	Ombitasvir, Paritaprevir, and Ritonavir may increase the serum concentration of HYDROcodone. Management: Reduce the hydrocodone dose by 50% during concurrent use of ombitasvir, paritaprevir, and ritonavir; monitor closely for both analgesic effectiveness and for signs of toxicity or withdrawal.
Iloperidone	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor.
Ivacaftor	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations.
Ivosidenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivosidenib. Management: Avoid use of a strong CYP3A4 inhibitor with ivosidenib whenever possible. When combined use is required, reduce the ivosidenib dose to 250 mg once daily. Drugs listed as exceptions are discussed in further detail in separate drug interaction monographs.
Ixabepilone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone.
Ketoconazole (Systemic)	Antihepaciviral Combination Products may increase the serum concentration of Ketoconazole (Systemic). Ketoconazole (Systemic) may increase the serum concentration of Antihepaciviral Combination Products. Specifically, ketoconazole may increase serum concentrations of paritaprevir. Management: Limit the dose of ketoconazole to 200 mg per day in patients taking antihepaciviral combination products. Additionally, monitor for increased ketoconazole effects/toxicities and for increased paritaprevir effects/toxicities.
Larotrectinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Increase to previous dose after stopping the inhibitor after a period of 3 to 5 times the inhibitor half-life.
Levomilnacipran	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors.
Losartan	Antihepaciviral Combination Products may increase the serum concentration of Losartan. Management: Per antihepaciviral combination product US prescribing information, consider decreasing the losartan dose and monitoring for evidence of hypotension and worsening renal function if these agents are used in combination.
Manidipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inhibitors. If combined, monitor closely for increased manidipine effects and toxicities. Manidipine dose reductions may be required.
Maraviroc	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min.
Meperidine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Meperidine. Management: Consider reducing meperidine dose if concomitant use with strong CYP3A4 inhibitors is required. Monitor for signs and symptoms of respiratory depression and sedation when these agents are combined.
MethylPREDNISolone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects.
Midostaurin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and strong CYP3A4 inhibitors if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Exceptions are discussed in separate monographs.
MiFEPRIStone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone. Management: Limit mifepristone adult dose, when used for treatment of hyperglycemia in Cushing's syndrome, to a maximum of 600 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication.
MiFEPRIStone	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus.
Mirodenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination.
Nilotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Management: Avoid if possible. If combination needed, decrease nilotinib to 300 mg once/day for patients with resistant or intolerant Ph+ CML or to 200 mg once/day for patients with newly diagnosed Ph+ CML in chronic phase. Exceptions discussed in separate monograph.
Olaparib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 100 mg twice daily.
OxyCODONE	CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased.
Panobinostat	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor.
Pexidartinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pexidartinib. Management: Avoid use of pexidartinib with strong CYP3A4 inhibitors if possible. If combined use cannot be avoided, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg/day to 200 mg/day.
Pimavanserin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin. Management: Decrease the pimavanserin dose to 10 mg daily when combined with strong CYP3A4 inhibitors.
Piperaquine	CYP3A4 Inhibitors (Strong) may enhance the QTc-prolonging effect of Piperaquine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Piperaquine. Management: Avoid concomitant use of piperaquine and strong CYP3A4 inhibitors when possible. If the combination cannot be avoided, frequent ECG monitoring is recommended due to the risk for QTc prolongation. Exceptions are discussed separately.
PONATinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor.
Pravastatin	Antihepaciviral Combination Products may increase the serum concentration of Pravastatin. Management: Limit the pravastatin dose to a maximum of 40 mg per day when used with antihepaciviral combination products and monitor patients for evidence of pravastatin toxicities (eg, myopathy).
QUEtiapine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of QUEtiapine. Management: In quetiapine treated patients, reduce quetiapine to one-sixth of regular dose after starting strong CYP3A4 inhibitor. In those on strong CYP3A4 inhibitors, start quetiapine at lowest dose and up-titrate as needed. Exceptions discussed separately.
Reboxetine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine.
Ribociclib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ribociclib. Management: Avoid use of ribociclib with strong CYP3A4 inhibitors when possible; if combined use cannot be avoided, reduce ribociclib dose to 400 mg once daily. Exceptions are discussed in separate monographs.
Riociguat	Antihepaciviral Combination Products may increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times daily. Patients receiving such a combination should also be monitored closely for signs or symptoms of hypotension.
Ruxolitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details.
SAXagliptin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling.
Sildenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary hypertension should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, starting adult dose should be reduced to 25 mg. Maximum adult dose with ritonavir or cobicistat is 25 mg per 48 hours.
Solifenacin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Solifenacin. Management: Limit solifenacin doses to 5 mg daily when combined with strong CYP3A4 inhibitors.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
SUFentanil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUFentanil. Management: If a strong CYP3A4 inhibitor is initiated in a patient on sufentanil, consider a sufentanil dose reduction and monitor for increased sufentanil effects and toxicities (eg, respiratory depression).
SUNItinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, sunitinib dose decreases are recommended, and vary by indication. See full monograph for details.
Tadalafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Recommendations regarding use of tadalafil in patients also receiving strong CYP3A4 inhibitors may vary based on indication and/or international labeling. Consult appropriate product labeling.
Temsirolimus	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inhibitors whenever possible. If combined, decrease temsirolimus dose to 12.5 mg per week and monitor patients for increased temsirolimus effects and toxicities.
Tezacaftor	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tezacaftor. Management: When combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor alone should be administered.
Thiotepa	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inhibitors. If concomitant use is unavoidable, monitor for adverse effects and decreased efficacy.
Tofacitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full monograph for details.
Tolterodine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor.
Toremifene	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Management: Use of toremifene with strong CYP3A4 inhibitors should be avoided if possible. If coadministration is necessary, monitor for increased toremifene toxicities, including QTc interval prolongation. Exceptions are discussed in separate monograph.
TraZODone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraZODone. Management: Consider the use of a lower trazodone dose and monitor for increased trazodone effects (eg, sedation, QTc prolongation) if combined with strong CYP3A4 inhibitors.
Valbenazine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Valbenazine. Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors.
Valsartan	Antihepaciviral Combination Products may increase the serum concentration of Valsartan. Management: Per antihepaciviral combination product US prescribing information, consider decreasing the valsartan dose and monitoring for evidence of hypotension and worsening renal function if these agents are used in combination.
Vardenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vardenafil. Management: Recommendations regarding concomitant use of vardenafil with strong CYP3A4 inhibitors may vary depending on brand name (e.g., Levitra, Staxyn) or by international labeling. See full drug interaction monograph for details.
Vemurafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with strong CYP3A4 inhibitors when possible. Consider use of an alternative that is not a strong inhibitor of CYP3A4 as clinically appropriate. Exceptions are discussed in separate monographs.
Venetoclax	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: This combination is contraindicated during venetoclax initiation and ramp-up in patients with CLL/SLL. Reduced venetoclax doses are required during ramp-up for patients with AML, and reduced doses are required for all patients during maintenance therapy.
Venetoclax	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors.
Vilazodone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg daily in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor.
Voriconazole	Antihepaciviral Combination Products may decrease the serum concentration of Voriconazole. Management: Concurrent use of voriconazole with antihepaciviral combination products should be avoided unless the patient-specific benefit/risk ratio justifies the use of voriconazole. Decreased efficacy of voriconazole is possible.
Zopiclone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined.
Zuclopenthixol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity.
Risk Factor X (Avoid combination)
Acalabrutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Acalabrutinib.
Ado-Trastuzumab Emtansine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component.
Alfuzosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin.
Aprepitant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant.
Astemizole	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Astemizole. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Asunaprevir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir.
Asunaprevir	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir.
Atazanavir	May increase the serum concentration of Ombitasvir, Paritaprevir, and Ritonavir. Specifically, the paritaprevir component may increase significantly.
AtorvaSTATin	Antihepaciviral Combination Products may increase the serum concentration of AtorvaSTATin.
Avanafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
Axitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended.
Barnidipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine.
Blonanserin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin.
Bosutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib.
Bromocriptine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine.
Budesonide (Systemic	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic).
Cisapride	Antihepaciviral Combination Products may increase the serum concentration of Cisapride.
Cobimetinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib.
Colchicine	Antihepaciviral Combination Products may increase the serum concentration of Colchicine.
Conivaptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan.
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of Antihepaciviral Combination Products.
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Antihepaciviral Combination Products.
Dabrafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib.
Dapoxetine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine.
Domperidone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Dronedarone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Elagolix	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix.
Eletriptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan.
Eplerenone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone.
Ergot Derivatives	Antihepaciviral Combination Products may increase the serum concentration of Ergot Derivatives. Exceptions: Cabergoline; Nicergoline; Pergolide.
Ethinyl Estradiol	May enhance the hepatotoxic effect of Antihepaciviral Combination Products. Management: Use of ethinyl estradiol must be discontinued prior to use of this combination; ethinyl estradiol can be restarted 2 weeks after cessation of the antihepaciviral combination product.
Everolimus	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus.
Everolimus	Antihepaciviral Combination Products may increase the serum concentration of Everolimus.
Flibanserin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin.
Fluticasone (Nasal)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal).
Fosaprepitant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fosaprepitant.
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Grazoprevir	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Grazoprevir.
Halofantrine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Ibrutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: Avoid concomitant use of ibrutinib and strong CYP3A4 inhibitors. If a strong CYP3A4 inhibitor must be used short-term (eg, anti-infectives for 7 days or less), interrupt ibrutinib therapy until the strong CYP3A4 inhibitor is discontinued.
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Irinotecan Products	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products.
Isavuconazonium Sulfate	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4.
Ivabradine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine.
Lapatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor.
Lefamulin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets and strong inhibitors of CYP3A4.
Lercanidipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine.
Lomitapide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide.
Lopinavir	May increase the serum concentration of Antihepaciviral Combination Products. Specifically, the serum concentrations of the paritaprevir component may increase significantly.
Lovastatin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin.
Lurasidone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone.
Macitentan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan.
Midazolam	Antihepaciviral Combination Products may increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with antihepaciviral combination products. When used with intravenous midazolam, monitor for increased midazolam effects (eg, sedation, respiratory depression) and consider using a reduced midazolam dose.
Naloxegol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol.
Neratinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Neratinib.
NiMODipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine.
Nisoldipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine.
Palbociclib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib.
PAZOPanib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib.
PAZOPanib	BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib.
Pimozide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide.
QuiNINE	Antihepaciviral Combination Products may increase the serum concentration of QuiNINE.
Radotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Radotinib.
Ranolazine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine.
Red Yeast Rice	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased.
Regorafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib.
Revefenacin	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin.
Rilpivirine	Antihepaciviral Combination Products may increase the serum concentration of Rilpivirine.
Rivaroxaban	Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Rivaroxaban.
Rupatadine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rupatadine.
Salmeterol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol.
Silodosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin.
Simeprevir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir.
Simvastatin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin.
Sirolimus	Antihepaciviral Combination Products may increase the serum concentration of Sirolimus.
Sonidegib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib.
Suvorexant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant.
Tacrolimus (Systemic)	Ombitasvir, Paritaprevir, and Ritonavir may increase the serum concentration of Tacrolimus (Systemic).
Tamsulosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin.
Terfenadine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Terfenadine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Ticagrelor	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor.
Tolvaptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan.
Topotecan	BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan.
Topotecan	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan.
Trabectedin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin.
Triazolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triazolam.
Udenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil.
Ulipristal	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity.
VinCRIStine (Liposomal)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal).
VinCRIStine (Liposomal)	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal).
Vinflunine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine.
Vorapaxar	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar.
Voxilaprevir	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir.

Monitoring Parameters:

Manufacturer's labeling:

Baseline hepatic function tests & during the first 4 weeks of therapy, then periodically during therapy, especially in patients taking efavirenz or in women taking concomitant Ethinyl estradiol products.
Serum HCV-RNA at baseline & at the end of treatment, during treatment follow-up, & when clinically indicated.
Prior to initiation, Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc).
Examine for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment & during post-treatment follow-up, in patients with serologic evidence of hepatitis B virus (HBV) infection.

Alternate recommendations:

Baseline (within 12 weeks prior to starting antiviral therapy):
- CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST & alkaline phosphatase), calculated GFR.
Baseline (at any time prior to starting antiviral therapy):
- HCV genotype and subtype, quantitative HCV viral load.

During therapy:

CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy, and as clinically indicated).
Quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy).
Repeat testing is recommended after 2 additional weeks of treatment (treatment week 6) if quantitative HCV viral load is detectable at treatment week 4.
In patients with diabetes, examine blood glucose & for signs/symptoms of hypoglycemia.

How to administer Viekirax (Ombitasvir, paritaprevir, and ritonavir)?

P/O:

Administer with a meal in the morning.

Mechanism of action of Viekirax (Ombitasvir, paritaprevir, and ritonavir):

Combination of 2 antiviral hepatitis C viruses agents that are direct-acting and have distinct mechanisms.
Ombitasvir blocks HCV NS5A replication and interferes with virion assembly.
Paritaprevir inhibits HCVNS3/4A protease, and interferes HCV coded polyprotein destruction necessary for viral replication.
Ritonavir is not active against HCV.
Ritonavir, a powerful CYP3A inhibitor, increases plasma drug concentrations of paritaprevir (peak and trough) and overall drug exposure (ie AUC).

Absorption:

Well absorbed when administered with food

Protein binding:

Ombitasvir:
- 99.9 percent.
Paritaprevir:
- ~98 percent.
Ritonavir:
- >99 percent.

Metabolism:

Ombitasvir:
- Metabolized by amide hydrolysis & oxidative metabolism
Paritaprevir:
- Metabolized by CYP3A4 & to a lesser extent CYP3A5
Ritonavir:
- Metabolized by CYP3A & to a lesser extent CYP2D6
Bioavailability:
- Ombitasvir: 48 percent
- Paritaprevir: 53 percent
- Ritonavir: No data available
Half-life elimination:
- Ombitasvir: 21-25 hours
- Paritaprevir: 5.5 hours
- Ritonavir: 4 hours
Time to peak:
- Ombitasvir, paritaprevir, ritonavir: 4-5 hours

Excretion:

Ombitasvir:
- Feces (90.2 percent, mainly as unchanged drug)
- Urine (1.91 percent, mainly as unchanged drug)
Paritaprevir:
- Feces (88 percent, mainly as metabolites)
- Urine (8.8 percent, mainly as metabolites)
Ritonavir:
- Feces (86.4 percent)
- Urine (11.3 percent)

International Brands of Ombitasvir, paritaprevir, and ritonavir:

Technivie
Viekirax

Ombitasvir, paritaprevir, and ritonavir Brand Names in Pakistan:

No Brands Available in Pakistan.