Saquinavir (Invirase) - Uses, Class, Dose, Side effects, MOA

Saquinavir (Invirase) belongs to the class of antiretroviral drugs called protease inhibitors. It is indicated for the treatment and prevention of HIV-1 infection in combination with ritonavir or other antiretroviral medications.

Saquinavir (Invirase) Uses:

HIV-1 infection:
- It is indicated for the treatment of HIV-1 infection in adults (>16 years) combined with ritonavir and other antiretroviral agents

Saquinavir (Invirase) Dose in Adults

Note:

Do ECG before starting therapy; do not begin therapy if pretreatment QT interval ≥450 msec.
Saquinavir should always be used in combination with ritonavir;
cobicistat is not interchangeable with ritonavir to increase systemic exposure.

Saquinavir (Invirase) Dose in the treatment of HIV-1 infection: Oral:

Usual dosage:
- 1,000 mg twice daily given combined with ritonavir 100 mg twice daily.
- For patients already taking ritonavir 100 mg twice daily as part of their antiretroviral regimen, no additional ritonavir is required.
- Treatment-naive patients or patients switching from a regimen containing delavirdine.

Note:

Patients with recent exposure (without washout) to a ritonavir or non-nucleoside reverse transcriptase inhibitor-based regimen (not including delavirdine or rilpivirine) can receive usual initial dosing (ie, saquinavir 1,000 mg twice daily combined with ritonavir 100 mg twice daily).
Initial: Saquinavir 500 mg twice daily given combined with ritonavir 100 mg twice daily for 7 days.
Maintenance:
- Saquinavir 1,000 mg twice daily given combined with ritonavir 100 mg twice daily.

Saquinavir (Invirase) Dose in Childrens

Note:

ECG should be done before starting therapy; do not start therapy if pretreatment QT interval >450 msec or if there is a diagnosis of long QT syndrome.
Saquinavir should only be used in regimens that include ritonavir "booster doses" so that adequate saquinavir serum concentrations are achieved; do not use without ritonavir booster doses.

Saquinavir (Invirase) Dose in the treatment of HIV-1 Infection:

Use in combination with other antiretroviral agents.

Infants and Children <2 years:
- Not approved for use; the appropriate dose is not known
Children ≥2 years and Adolescents <16 years:
- Treatment-experienced, ritonavir-boosted regimen:
  - 5 kg to <15 kg:
    - Saquinavir 50 mg/kg/dose orally twice daily plus ritonavir 3 mg/kg/dose twice daily
  - 15 kg to <40 kg:
    - Saquinavir 50 mg/kg/dose (maximum dose: 1,000 mg/dose) orally twice daily plus ritonavir 2.5 mg/kg/dose twice daily
  - ≥40 kg:
    - Saquinavir 1000 mg plus ritonavir 100 mg orally twice daily
Adolescents ≥16 years:
- Oral: 1,000 mg twice daily given combined with ritonavir 100 mg twice daily.
- For patients already taking ritonavir 100 mg twice daily as part of their antiretroviral regimen, no additional ritonavir is needed.
Treatment-naive patients or patients switching from a regimen containing delavirdine or rilpivirine:
- Adolescents >16 years:

Note:

Patients with recent exposure (without washout) to a ritonavir or non-nucleoside reverse transcriptase inhibitor-based regimen (not including delavirdine or rilpivirine) may receive usual initial dosing (ie, saquinavir 1,000 mg twice daily combined with ritonavir 100 mg twice daily).
- - Initial: Saquinavir 500 mg twice daily given combined with ritonavir 100 mg twice daily for 7 days
  - Maintenance: Saquinavir 1,000 mg twice daily given combined with ritonavir 100 mg twice daily

Saquinavir (Invirase) Pregnancy Risk Category: B

Saquinavir is a drug that has low levels of transfer to the human placenta.
The data from the antiretroviral pregnant registry do not provide enough information to assess human teratogenic risks.
Although maternal antiretroviral treatment (ART) may increase preterm birth rates, information is not available due to the variability in maternal factors (disease severity and gestational age at the initiation of therapy).
Some studies have reported an increased risk of stillbirth, low birthweight, and small gestational age infants. However, not all studies have confirmed this.
Maternal ART is beneficial and should be continued.
All infants who have been exposed to antiretroviral medication should be followed up for a long time.
Children with significant organ system abnormalities (especially the heart or CNS) that are not of known etiology should be examined for possible mitochondrial dysfunction.
Protease inhibitors have been shown to reduce hyperglycemia, diabetes mellitus recurrence, and diabetic ketoacidosis. It is unclear if this risk increases during pregnancy.
Health and Human Services (HHS), Perinatal HIV Guidelines, do not recommend saquinavir use in pregnancy.
Females who get pregnant with saquinavir should switch to another recommended regimen.
According to available data, dose adjustments for pregnant patients are not necessary.
To keep HIV-positive pregnant women under the control and reduce the chance of perinatal transmission, it is generally recommended that ART be performed.
Monitoring during pregnancy is more common than monitoring in adults who are not pregnant.
All HIV-positive women should continue ART after delivery. ART can also be modified after delivery.

Saquinavir use during breastfeeding:

It is not known if breast milk contains saquinavir.
Postnatal HIV transmission is possible even if infant or maternal antiretroviral treatment is not stopped.
The multiclass-resistant virus was also detected in infants breastfeeding despite the fact that maternal therapy has not been effective.
To reduce HIV transmission, women with HIV should not breastfeed in the United States.

Saquinavir (Invirase) Dose in Kidney Disease:

No dosage adjustment required; use cautiously in severe renal impairment or ESRD (has not been studied).

Saquinavir (Invirase) Dose in Liver disease:

Mild to moderate impairment (Child-Pugh classes A and B):
- No dose adjustment required.
Severe impairment (Child-Pugh class C):
- Use is contraindicated.

Incidence data for saquinavir soft gel capsule formulation (no longer available) in combined with ritonavir:

Common Side Effects of Saquinavir (Invirase):

Gastrointestinal:
- Nausea

Less Common Side Effects of Saquinavir (Invirase):

Cardiovascular:
- Chest Pain
Central Nervous System:
- Fatigue
- Anxiety
- Depression
- Headache
- Insomnia
- Pain
- Paresthesia
Dermatologic:
- Pruritus
- Skin Rash
- Eczema
- Cheilosis
- Xeroderma
- Warts
Endocrine & Metabolic:
- Lipodystrophy
- Hyperglycemia
- Change In Libido
- Hypoglycemia
- Hyperkalemia
Gastrointestinal:
- Diarrhea
- Vomiting
- Abdominal Pain
- Constipation
- Abdominal Distress
- Decreased Appetite
- Dysgeusia
- Dyspepsia
- Flatulence
- Increased Serum Amylase
- Oral Mucosa Ulcer
Hepatic:
- Increased Serum ALT
- Increased Serum AST
- Increased Serum Bilirubin
Infection:
- Influenza
Neuromuscular & Skeletal:
- Back Pain
- Increased Creatine Phosphokinase
- Weakness
Respiratory:
- Pneumonia
- Bronchitis
- Sinusitis
Miscellaneous:
- Fever

Side effects of Saquinavir (Invirase) - Frequency of side effects not defined:

Cardiovascular:
- Heart Valve Disease (Including Murmur)
- Hypertension
- Hypotension
- Peripheral Vasoconstriction
- Prolongation P-R Interval On ECG
- Prolonged Q-T Interval On ECG
- Syncope
- Thrombophlebitis
Central Nervous System:
- Agitation
- Amnesia
- Ataxia
- Colic
- Confusion
- Drowsiness
- Hallucination
- Hyperreflexia
- Hyporeflexia
- Neuropathy
- Poliomyelitis
- Progressive Multifocal Leukoencephalopathy
- Psychosis
- Seizure
- Speech Disturbance
Dermatologic:
- Alopecia
- Bullous Dermatitis
- Dermal Ulcer
- Dermatitis
- Erythema
- Maculopapular Rash
- Skin Photosensitivity
- Stevens-Johnson Syndrome
- Urticaria
Endocrine & Metabolic:
- Dehydration
- Diabetes Mellitus
- Electrolyte Disturbance
- Increased Gamma-Glutamyl Transferase
- Increased Lactate Dehydrogenase
- Increased Thyroid Stimulating Hormone Level
Gastrointestinal:
- Bloody Stools
- Dysphagia
- Esophagitis
- Gastritis
- Intestinal Obstruction
- Pancreatitis
- Stomatitis
Genitourinary:
- Benign Prostatic Hypertrophy
- Hematuria
- Impotence
- Urinary Tract Infection
Hematologic & Oncologic:
- Acute Myelocytic Leukemia
- Anemia (Including Hemolytic)
- Leukopenia
- Neutropenia
- Pancytopenia
- Rectal Hemorrhage
- Splenomegaly
- Thrombocytopenia
Hepatic:
- Ascites
- Hepatic Disease (Exacerbation)
- Hepatitis
- Hepatomegaly
- Hepatosplenomegaly
- Increased Serum Alkaline Phosphatase
- Jaundice
Immunologic:
- Immune Reconstitution Syndrome
Infection:
- Infection (Bacterial
- Fungal
- Viral)
Neuromuscular & Skeletal:
- Arthritis
Ophthalmic:
- Blepharitis
- Visual Disturbance
Otic:
- Auditory Impairment
- Otitis
- Tinnitus
Renal:
- Nephrolithiasis
Respiratory:
- Cyanosis
- Dyspnea
- Hemoptysis
- Pharyngitis
- Upper Respiratory Tract Infection

Contraindications to Saquinavir (Invirase):

Hypersensitivity to saquinavir or saquinavir mésylate or any other component of the formulation (eg, Stevens-Johnson Syndrome, anaphylactic reaction)
congenital QT prolongation,
Refractory hypokalemia and hypomagnesemia
Concurrent use of other medications can increase plasma concentrations of saquinavir and prolong the QT interval.
Complete AV block without implanted pacemaker or patients at high risk for complete AV Block
Grave hepatic impairment
Coadministration of saquinavir/ritonavir and CYP3A substrats, for example:
- alfuzosin,
- amiodarone,
- atazanavir,
- bepridil,
- chlorpromazine,
- cisapride,
- Clarithromycin
- clozapine,
- dasatinib,
- disopyramide,
- dofetilide,
- ergot derivatives [dihydroergotamine, ergonovine, ergotamine, methylergonovine],
- Erythromycin
- flecainide,
- Halofantrine
- haloperidol
- lidocaine [systemic],
- lovastatin,
- lurasidone,
- midazolam [oral],
- pentamidine,
- phenothiazines,
- pimozide,
- propafenone,
- quinidine,
- Quinine
- rifampin,
- rilpivirine [concomitant use or when switching to saquinavir/ritonavir without a >=2-week washout period],
- sertindole
- sildenafil [when used to treat pulmonary hypertension (eg, Revatio)].
- simvastatin,
- sunitinib,
- tacrolimus,
- thioridazine,
- trazodone
- triazolam,
- ziprasidone.

Canadian labeling: Additional contraindications not in US labeling

Concomitant use with quetiapine, procainamide, sotalol, astemizole, or terfenadine;
Concurrent use of medications that increase the plasma concentrations of saquinavir and prolong the PR interval is not recommended.
Extended QT

Warnings and precautions

Modified cardiac conduction
- Saquinavir/ritonavir prolongs QT intervals, possibly leading to torsade des pointes. It also prolongs PR intervals, potentially leading in heart block.
- Reports of AV block in the second or third degree have been rare.
- Before starting saquinavir/ritonavir treatment, an ECG should be done on all patients. Patients with a baseline QT interval greater than 450 msec or with long QT syndrome must have this ECG performed.
- If baseline QT interval <450 msec, may start saquinavir/ritonavir, but a subsequent ECG is recommended after ~10 days of therapy.
- Patients who are already taking saquinavir/ritonavir and need concurrent therapy, such as patients who have a baseline QT interval of 450msec or more, can initiate concomitant therapy. However, a subsequent ECG should be performed after three to four days.
- Therapy should be stopped if the QT interval prolongs beyond baseline by more than 20 msec
- Patients at higher risk of QT-interval prolongation or PR-interval prolongation are those who have heart failure, bradyarrhythmias or hepatic impairment, electrolyte abnormalities and ischemic heart disease, cardiac disease, cardiomyopathy, structure heart disease or patients with pre-existing cardiac conduction disorders.
- These patients should be monitored with an ECG.
- If significant arrhythmias or prolonged PR occur, stop therapy.
Fat redistribution
- Redistribution of fat may occur (e.g., buffalo hump; peripheral wasting with an increased abdominal girth; cushingoid appearance).
Immune reconstitution syndrome:
- The immune reconstitution syndrome may occur in patients who have received HIV treatment. This can lead to an inflammatory response to an indolent, residual opportunistic virus or activation of autoimmune disorders (eg Graves' disease or polymysitis) during therapy.
- Additional evaluation and treatment may still be necessary.
Increasing cholesterol
- There have been reports of an increase in total cholesterol and triglycerides. Screening should be performed before and during treatment.
Photosensitivity reactions
- Photosensitivity reactions may occur (eg, sun exposure can cause severe sunburns, skin rash or reddening, or itching).
- Patients should be advised to avoid sunlight and artificial light sources (eg sunlamps, tanning beds/booths) and to wear protective clothing, wide-brimmed caps, sunglasses and lip sunscreen (SPF >=15).
- Use sunscreen (broad-spectrum or physical sunscreen [preferred]) or sunblock with SPF>=15.
Diabetes:
- Patients who have received protease inhibitors have experienced changes in glucose tolerance, hyperglycemia and exacerbation or new-onset diabetes mellitus.
Electrolyte imbalances:
- Before treatment, correct electrolyte imbalances and monitor potassium levels and magnesium levels throughout therapy.
Hemophilia A and B:
- Patients with hemophilia A and B should be cautious; there have been reports of increased bleeding after receiving protease inhibitor therapy.
Hepatic impairment
- Patients with mild-to-moderate underlying liver disease such as cirrhosis or chronic alcoholism should be cautious.
- It can cause portal hypertension, hepatitis and jaundice.
- It is contraindicated for severe hepatic impairment.
- If severe hepatotoxicity is observed, discontinue saquinavir/ritonavir.
Lactose intolerance:
- Contains lactose. Not recommended for patients with rare hereditary conditions of lactose intolerance such as Lapp lactase deficit, glucose-galactose malabsorption.

Saquinavir: Drug Interaction

Risk Factor C (Monitor therapy)
Abacavir	Protease Inhibitors may decrease the serum concentration of Abacavir.
Alosetron	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron.
AmLODIPine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of AmLODIPine.
Antidiabetic Agents	Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
Apixaban	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Apixaban.
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.
Betamethasone (Ophthalmic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Ophthalmic).
Bictegravir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bictegravir.
Bitter Orange	May increase the serum concentration of Saquinavir.
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.
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	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Buprenorphine.
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.
Cat's Claw	May increase the serum concentration of Saquinavir.
Cinacalcet	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cinacalcet.
Citalopram	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Citalopram.
Clorazepate	Saquinavir may increase the serum concentration of Clorazepate.
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.
Cyclophosphamide	Protease Inhibitors may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
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	Saquinavir may increase the serum concentration of DiazePAM.
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.
Enfuvirtide	Protease Inhibitors may increase the serum concentration of Enfuvirtide. Enfuvirtide may increase the serum concentration of Protease Inhibitors.
Estazolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estazolam.
Estrogen Derivatives	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estrogen Derivatives.
Etravirine	Protease Inhibitors may decrease the serum concentration of Etravirine. This effect is anticipated with darunavir, saquinavir, and lopinavir (with low-dose ritonavir). Etravirine may increase the serum concentration of Protease Inhibitors. This effect is anticipated with nelfinavir. Management: Low-dose ritonavir boosting must be used when any protease inhibitor is used with etravirine. Avoid use of etravirine in combination with atazanavir, fosamprenavir, full-dose ritonavir (600 mg twice daily, in adults), or tipranavir.
Evogliptin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Evogliptin.
Fluconazole	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Flurazepam	Saquinavir may increase the serum concentration of Flurazepam.
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.
Histamine H2 Receptor Antagonists	May increase the serum concentration of Saquinavir.
HYDROcodone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of HYDROcodone.
Idelalisib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Idelalisib.
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.
Levomethadone	Saquinavir may decrease the serum concentration of Levomethadone.
Lopinavir	May enhance the QTc-prolonging effect of Saquinavir.
Lumefantrine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
Mirtazapine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirtazapine.
Naldemedine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naldemedine.
Nalfurafine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nalfurafine.
Nevirapine	May decrease the serum concentration of Saquinavir.
Ondansetron	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Orlistat	May decrease the serum concentration of Antiretroviral Agents.
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 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
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.
Pravastatin	Saquinavir may decrease the serum concentration of Pravastatin. This effect has only been demonstrated with saquinavir/ritonavir. The individual contributions of saquinavir and ritonavir are unknown.
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.
Proton Pump Inhibitors	May increase the serum concentration of Saquinavir.
QT-prolonging Antidepressants (Moderate Risk)	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Exceptions: Citalopram.
QT-prolonging Antipsychotics (Moderate Risk)	May enhance the QTc-prolonging effect of Saquinavir. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: CloZAPine; Pimozide; QUEtiapine; Thioridazine.
QT-prolonging Class IC Antiarrhythmics (Moderate Risk)	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
QT-prolonging Quinolone Antibiotics (Moderate Risk)	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
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.
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)	Protease Inhibitors may decrease the metabolism of Tacrolimus (Topical).
Tasimelteon	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon.
Telithromycin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Telithromycin.
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.
Tricyclic Antidepressants	Protease Inhibitors may increase the serum concentration of Tricyclic Antidepressants.
Upadacitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Upadacitinib.
Valproate Products	Protease Inhibitors may decrease the serum concentration of Valproate Products.
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.
Voriconazole	Saquinavir may enhance the QTc-prolonging effect of Voriconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Warfarin	Saquinavir may increase the serum concentration of Warfarin.
Zidovudine	Protease Inhibitors may decrease the serum concentration of Zidovudine.
Zolpidem	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zolpidem.
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	Saquinavir may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10 mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer saquinavir 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.
ALPRAZolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of ALPRAZolam. Management: Consider using an alternative agent that is less likely to interact. If combined, monitor for increased therapeutic/toxic effects of alprazolam if combined with a strong CYP3A4 inhibitor.
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.
AtorvaSTATin	Protease Inhibitors may increase the serum concentration of AtorvaSTATin. Management: See full monograph for recommended dose limits. Avoid atorvastatin with tipranavir/ritonavir.
Bedaquiline	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Bedaquiline. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Bedaquiline. Management: Consider alternatives to this drug combination and avoid use for more than 14 days. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Bosentan	May decrease the serum concentration of Saquinavir. Saquinavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking saquinavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting saquinavir/ritonavir; wait at least 10 days before restarting bosentan.
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.
Calcium Channel Blockers (Nondihydropyridine)	Protease Inhibitors may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Increased serum concentrations of the calcium channel blocker may increase risk of AV nodal blockade. Management: Avoid concurrent use when possible. If used, monitor for CCB toxicity. The manufacturer of atazanavir recommends a 50% dose reduction for diltiazem be considered. Saquinavir, tipranavir, and darunavir/cobicistat use with bepridil is contraindicated.
CarBAMazepine	May increase the metabolism of Protease Inhibitors. Protease Inhibitors may decrease the metabolism of CarBAMazepine.
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	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ceritinib. Management: Avoid concomitant use of ceritinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease ceritinib dose by one-third and monitor patients for ceritinib toxicities including QTc prolongation and arrhythmias.
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.
Colchicine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details.
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	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease crizotinib dose to 250 mg daily. Monitor patients for crizotinib toxicities including QTc prolongation and arrhythmias.
CycloSPORINE (Systemic)	Protease Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Protease Inhibitors.
CycloSPORINE (Systemic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of CycloSPORINE (Systemic).
CYP3A4 Inducers (Strong)	May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
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.
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.
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	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Delamanid. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Delamanid. Management: If coadministration of delamanid with any strong CYP3A4 inhibitor is considered necessary, very frequent monitoring of ECGs is recommended throughout the full delamanid treatment period.
Delavirdine	Protease Inhibitors may decrease the serum concentration of Delavirdine. Delavirdine may increase the serum concentration of Protease Inhibitors.
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.
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.
Efavirenz	Saquinavir may enhance the adverse/toxic effect of Efavirenz. Efavirenz may decrease the serum concentration of Saquinavir. Management: When used together with efavirenz, saquinavir should not be used as the sole protease inhibitor. Appropriate doses of the combination of efavirenz with saquinavir/ritonavir have not been established.
Elagolix	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elagolix. Management: Use of the elagolix 200 mg twice daily dose with a strong CYP3A4 inhibitor for longer than 1 month is not recommended. Limit combined use of the elagolix 150 mg once daily dose with a strong CYP3A4 inhibitor to a maximum of 6 months.
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	Saquinavir may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with saquinavir and 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.
Encorafenib	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Encorafenib. Management: Avoid using strong CYP3A4 inhibitors together with encorafenib if possible. If the combination must be used, reduce the encorafenib dose and monitor QT interval. See monograph for details.
Enzalutamide	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring.
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).
Estrogen Derivatives (Contraceptive)	Protease Inhibitors may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use oral contraceptives containing at least 35mcg ethinyl estradiol with atazanavir/ritonavir, or no more than 30mcg in patients receiving atazanavir alone. Use of an alternative, non-hormonal contraceptive is recommended with other protease inhibitors.
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.
Garlic	May decrease the serum concentration of Protease Inhibitors. Management: Concurrent use of garlic supplements with protease inhibitors is not recommended. If this combination is used, monitor closely for altered serum concentrations/effects of protease inhibitors, and particularly for signs/symptoms of therapeutic failure.
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.
Gilteritinib	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Gilteritinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Gilteritinib. Management: Consider alternatives to the use of gilteritinib with strong CYP3A4 inhibitors that prolong the QTc interval whenever possible
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.
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.
Itraconazole	May increase the serum concentration of Saquinavir. Saquinavir may increase the serum concentration of Itraconazole. Management: Limit the adult maximum itraconazole dose to 200 mg/day in patients receiving saquinavir/ritonavir.
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	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ivosidenib. Management: Avoid using strong CYP3A4 inhibitors together with ivosidenib if possible. If the combination must be used, reduce the ivosidenib dose to 250 mg once daily.
Ixabepilone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone.
Ketoconazole (Systemic)	Saquinavir may increase the serum concentration of Ketoconazole (Systemic). Ketoconazole (Systemic) may increase the serum concentration of Saquinavir. Management: Limit the adult maximum ketoconazole dose to 200 mg/day in patients receiving saquinavir/ritonavir.
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.
Lorlatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with strong CYP3A4 inhibitors. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily, or from 75 mg once daily to 50 mg once daily.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
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.
Methadone	Saquinavir may enhance the QTc-prolonging effect of Methadone. Saquinavir may decrease the serum concentration of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation, ventricular arrhythmias, and opioid withdrawal symptoms. Patients with additional risk factors for QTc prolongation may be at even higher risk.
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	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Midostaurin. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Midostaurin. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk.
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.
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.
Mitotane	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.
Nefazodone	Protease Inhibitors may increase the serum concentration of Nefazodone. Management: Consider alternatives to, or reduced doses of, nefazodone in patients treated with HIV protease inhibitors. Monitor patients receiving these combinations closely for toxic effects of nefazodone.
Nilotinib	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Nilotinib. Management: Avoid concomitant use of nilotinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, nilotinib dose reductions are required. Monitor patients for nilotinib toxicities including QTc prolongation and arrhythmias.
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.
Osimertinib	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk.
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.
PAZOPanib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of PAZOPanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib adult dose to 400 mg. Further dose reductions may also be required.
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	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Piperaquine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Piperaquine. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk.
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.
Progestins (Contraceptive)	Saquinavir may decrease the serum concentration of Progestins (Contraceptive). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction.
Protease Inhibitors	May increase the serum concentration of other Protease Inhibitors. Management: Atazanavir--indinavir combination contraindicated. Tipranavir/ritonavir or atazanavir/ritonavir not recommended with other protease inhibitors (PI). Darunavir/cobicistat not recommended with PI that require boosting.Other combos may require dose changes.
QT-prolonging Class IA Antiarrhythmics (Highest Risk)	May enhance the QTc-prolonging effect of Saquinavir. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Disopyramide; QuiNIDine.
QT-prolonging Class III Antiarrhythmics (Highest Risk)	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Dronedarone.
QT-prolonging Kinase Inhibitors (Highest Risk)	May enhance the QTc-prolonging effect of QTprolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Ivosidenib.
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.
QUEtiapine	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QUEtiapine. Management: Reduce the quetiapine dose to one-sixth of the regular dose when combined with strong CYP3A4 inhibitors. Monitor patients for quetiapine toxicities, including QTc prolongation and torsades de pointes.
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.
Ribociclib	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ribociclib. Management: Avoid concomitant use of ribociclib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease the ribociclib dose to 400 mg daily. Monitor for ribociclib toxicities including QTc prolongation and arrhythmias.
Rifabutin	Saquinavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Saquinavir may increase the serum concentration of Rifabutin. Rifabutin may decrease the serum concentration of Saquinavir. Management: Reduce rifabutin doses. Saquinavir US labeling recommends a decrease of at least 75%, to 150 mg every other day or 3 times per week for adults. Clinical guidelines recommend 150 mg daily or 300 mg 3 times per week when used with saquinavir/ritonavir.
Riociguat	Protease Inhibitors may increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day (for adults). Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension.
Rosuvastatin	Protease Inhibitors may increase the serum concentration of Rosuvastatin. Management: Start at the lowest rosuvastatin dose and monitor for toxicity. See full drug interaction monograph for details.
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	Saquinavir may increase the serum concentration of Sildenafil. Management: Used for PAH: no dose adjustment recommended per US label, Canadian label recommends decrease to 20 mg twice/day. Used for ED: consider a lower starting dose of 25 mg with concurrent saquinavir.
Sirolimus	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sirolimus. Management: Consider avoiding concurrent use of sirolimus with strong CYP3A4 inhibitors in order to minimize the risk for sirolimus toxicity. Concomitant use of sirolimus and voriconazole or posaconazole is contraindicated.
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.
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).
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	Protease Inhibitors may enhance the adverse/toxic effect of Temsirolimus. Levels of sirolimus, the active metabolite, may be increased, likely due to inhibition of CYP-mediated metabolism.
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	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Toremifene. Management: Avoid concomitant use of toremifene and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, monitor patients for toremifene toxicities including QTc prolongation and TdP.
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.
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	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Vemurafenib. Management: Avoid concomitant use of vemurafenib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined monitor patients for vemurafenib toxicities including QTc prolongation and TdP.
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.
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.
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.
Alfuzosin	Protease Inhibitors may increase the serum concentration of Alfuzosin.
Amiodarone	Saquinavir may enhance the QTc-prolonging effect of Amiodarone. Saquinavir may increase the serum concentration of Amiodarone.
Antipsychotic Agents (Phenothiazines)	May enhance the arrhythmogenic effect of Saquinavir. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Exceptions: ChlorproMAZINE.
Aprepitant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant.
Astemizole	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Astemizole. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Astemizole.
Asunaprevir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir.
Atazanavir	Saquinavir may increase the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Saquinavir.
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	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Cisapride. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Cisapride.
Clarithromycin	Saquinavir may enhance the QTc-prolonging effect of Clarithromycin. Clarithromycin may increase the serum concentration of Saquinavir.
CloZAPine	Saquinavir may enhance the QTc-prolonging effect of CloZAPine.
Cobicistat	May increase the serum concentration of Saquinavir. However, the magnitude of this change is unclear, and dosing recommendations for this combination are not available.
Cobimetinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib.
Conivaptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan.
Dabrafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib.
Dapoxetine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine.
Darunavir	Saquinavir may decrease the serum concentration of Darunavir.
Dasatinib	May enhance the QTc-prolonging effect of Saquinavir. Saquinavir may increase the serum concentration of Dasatinib.
Disopyramide	Saquinavir may enhance the QTc-prolonging effect of Disopyramide. Saquinavir may increase the serum concentration of Disopyramide.
Domperidone	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Domperidone. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Domperidone.
Dronedarone	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Dronedarone. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dronedarone.
Eletriptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan.
Entrectinib	May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Entrectinib.
Eplerenone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone.
Ergot Derivatives	Protease Inhibitors may increase the serum concentration of Ergot Derivatives. Exceptions: Cabergoline; Nicergoline; Pergolide.
Erythromycin (Systemic	May enhance the QTc-prolonging effect of Saquinavir. Erythromycin (Systemic) may increase the serum concentration of Saquinavir.
Everolimus	CYP3A4 Inhibitors (Strong) 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)	Saquinavir may increase the serum concentration of Fusidic Acid (Systemic). Fusidic Acid (Systemic) may increase the serum concentration of Saquinavir.
Grazoprevir	Saquinavir may increase the serum concentration of Grazoprevir.
Halofantrine	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Halofantrine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Halofantrine.
Haloperidol	Saquinavir may enhance the QTc-prolonging effect of Haloperidol.
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.
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.
Lidocaine (Systemic)	Saquinavir may enhance the arrhythmogenic effect of Lidocaine (Systemic). Saquinavir may increase the serum concentration of Lidocaine (Systemic).
Lomitapide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide.
Lovastatin	Protease Inhibitors may increase the serum concentration of Lovastatin.
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	Protease Inhibitors may increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with all protease inhibitors. IV midazolam contraindicated with fosamprenavir and nelfinavir; other protease inhibitors recommend caution, close monitoring, and consideration of lower IV midazolam doses with concurrent use.
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.
Pentamidine (Systemic)	May enhance the QTc-prolonging effect of Saquinavir.
Pimozide	Protease Inhibitors may increase the serum concentration of Pimozide.
Pimozide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide.
Pimozide	May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk).
QT-prolonging Miscellaneous Agents (Highest Risk)	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Exceptions: Astemizole; Bedaquiline; Cisapride; Delamanid; Terfenadine.
QT-prolonging Miscellaneous Agents (Moderate Risk)	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Exceptions: Domperidone; Halofantrine; Midostaurin; Piperaquine; Toremifene.
QuiNIDine	Saquinavir may enhance the QTc-prolonging effect of QuiNIDine.
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.
RifAMPin	May enhance the adverse/toxic effect of Saquinavir. Specifically, the risk of hepatocellular toxicity may be increased. RifAMPin may decrease the serum concentration of Saquinavir.
Rilpivirine	Saquinavir may enhance the arrhythmogenic effect of Rilpivirine. Saquinavir may increase the serum concentration of Rilpivirine.
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.
Simeprevir	Protease Inhibitors may increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Protease Inhibitors.
Simvastatin	Protease Inhibitors may increase the serum concentration of Simvastatin.
Simvastatin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin.
Sonidegib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib.
St John's Wort	May increase the metabolism of Protease Inhibitors.
SUNItinib	Saquinavir may increase the serum concentration of SUNItinib.
Suvorexant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant.
Tacrolimus (Systemic)	Saquinavir may increase the serum concentration of Tacrolimus (Systemic).
Tamsulosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin.
Terfenadine	QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTcprolonging effect of Terfenadine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Terfenadine.
Thioridazine	Saquinavir may enhance the QTc-prolonging effect of Thioridazine.
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.
Tipranavir	May decrease the serum concentration of Protease Inhibitors.
Tolvaptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan.
Trabectedin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin.
TraZODone	Saquinavir may enhance the QTc-prolonging effect of TraZODone. Saquinavir may increase the serum concentration of TraZODone.
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).
Vinflunine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine.
Vorapaxar	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar.

Monitoring parameters:

Monitor ECG (before therapy and after 3 to 4 days of therapy [patients already receiving saquinavir/ritonavir and initiating concomitant QT prolonging therapy] or after ~10 days of therapy [patients initiating saquinavir/ritonavir]);
serum potassium and magnesium levels,
triglycerides and cholesterol (before starting and periodically during therapy);
viral load, CD4 count;
glucose

How to administer Saquinavir (Invirase)?

Oral:

Administer saquinavir and ritonavir at the same time and within 2 hours after a full meal.
Patients unable to swallow capsules may open capsules and mix contents with 15 mL of syrup (or sorbitol if diabetic or glucose intolerant) or with 3 teaspoons of jam.
Stir the mixture for 30 to 60 seconds and then administered entirely.
Suspension should be at room temperature before administration.
Do not crush tablets.

Mechanism of action of Saquinavir (Invirase):

It binds to the HIV-1 protease site and inhibits cleavage viral GagPol polyprotein precursors into functional proteins necessary for HIV infection.
This causes the formation of non-infectious, immature viral particles.

Absorption:

Poor;
increased with a high-fat meal

Distribution:

It does not distribute into CSF; partitions into tissues

Protein binding, plasma:

~98%

Metabolism:

Extensively hepatic via CYP3A4 to inactive mono- and dihydroxylated metabolites; extensive first-pass effect

Bioavailability:

Invirase: ~4% (increased in the presence of food);
The bioavailability of Invirase capsules and tablets are similar when administered with low dose ritonavir (ie, booster doses of ritonavir)

Half-life, serum:

1 to 2 hours

Excretion:

Feces (81% to 88%),
urine (1% to 3%) within 5 days

Clearance:

Children: Significantly higher than adults

International Brand Names of Saquinavir:

Invirase
Fortovase
Invest
Teravasa

Saquinavir Brand Names in Pakistan:

No Brands Available in Pakistan.

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Saquinavir (Invirase) - Uses, Class, Dose, Side effects, MOA

Saquinavir (Invirase) Uses:

HIV-1 infection:

Saquinavir (Invirase) Dose in Adults

Saquinavir (Invirase) Dose in the treatment of HIV-1 infection: Oral:

Saquinavir (Invirase) Dose in Childrens

Saquinavir (Invirase) Dose in the treatment of HIV-1 Infection:

Infants and Children <2 years:

Children ≥2 years and Adolescents <16 years:

Adolescents ≥16 years:

Treatment-naive patients or patients switching from a regimen containing delavirdine or rilpivirine:

Saquinavir (Invirase) Pregnancy Risk Category: B

Saquinavir use during breastfeeding:

Saquinavir (Invirase) Dose in Kidney Disease:

Saquinavir (Invirase) Dose in Liver disease:

Common Side Effects of Saquinavir (Invirase):

Gastrointestinal:

Less Common Side Effects of Saquinavir (Invirase):

Cardiovascular:

Central Nervous System:

Dermatologic:

Endocrine & Metabolic:

Gastrointestinal:

Hepatic:

Infection:

Neuromuscular & Skeletal:

Respiratory:

Miscellaneous:

Side effects of Saquinavir (Invirase) - Frequency of side effects not defined:

Cardiovascular:

Central Nervous System:

Dermatologic:

Endocrine & Metabolic:

Gastrointestinal:

Genitourinary:

Hematologic & Oncologic:

Hepatic:

Immunologic:

Infection:

Neuromuscular & Skeletal:

Ophthalmic:

Otic:

Renal:

Respiratory:

Contraindications to Saquinavir (Invirase):

Warnings and precautions

Modified cardiac conduction

Fat redistribution

Immune reconstitution syndrome:

Increasing cholesterol

Photosensitivity reactions

Diabetes:

Electrolyte imbalances:

Hemophilia A and B:

Hepatic impairment

Lactose intolerance:

Monitoring parameters:

How to administer Saquinavir (Invirase)?

Mechanism of action of Saquinavir (Invirase):

International Brand Names of Saquinavir:

Saquinavir Brand Names in Pakistan:

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