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Saquinavir Mesylate

Pronunciation: sa-KWIN-a-vir MES-i-late
Class: Protease inhibitor

Trade Names

Invirase
- Capsules, oral 200 mg
- Tablets, oral 500 mg

Pharmacology

Inhibits HIV protease, the enzyme required to form functional proteins in HIV-infected cells.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Bioavailability averaged 4%. Mean AUC increased from 24 ng•h/mL when administered under fasting conditions to 161 ng•h/mL when administered after a high-fat meal.

Distribution

Saquinavir is approximately 98% protein bound and Vd is 700 L.

Metabolism

Saquinavir undergoes extensive first-pass metabolism. Metabolism is CYP-450–mediated with the specific isoenzyme CYP3A4 responsible for more than 90% of the hepatic metabolism.

Elimination

Systemic Cl is rapid (1.14 L/h/kg after IV doses of 6, 36, and 72 mg). 88% was recovered in the feces; 1% was recovered in the urine.

Special Populations

Renal Function Impairment

Impact of renal impairment on elimination should be minimal.

Hepatic Function Impairment

Approximately 30% reduction in saquinavir exposure in patients with moderate hepatic impairment. No dosage adjustment is required in patients with mild or moderate hepatic impairment.

Elderly

Pharmacokinetics have not been sufficiently studied in patients older than 65 y of age.

Children

Pharmacokinetics have not been sufficiently studied in children.

Gender

Exposure is higher in women than in men (mean increases in AUC and C max are 56% and 26%, respectively). However, clinically significant differences in safety and efficacy between men and women at approved dosage regimens have not been reported.

Race

Effect of race on pharmacokinetics has not been evaluated.

Indications and Usage

Treatment of HIV-1 infection in adults (older than 16 y) in combination with ritonavir and other antiretroviral agents.

Contraindications

Complete AV block without implanted pacemakers, or at risk of complete AV block, congenital long QT syndrome, refractory hypokalemia or hypomagnesemia, or in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval; coadministration with CYP3A substrates (eg, alfuzosin, amiodarone, bepridil, cisapride, dofetilide, ergot derivatives, flecainide, lidocaine [systemic], lovastatin, midazolam [orally administered], pimozide, propafenone, quinidine, rifampin, sildenafil [for the treatment of pulmonary arterial hypertension], simvastatin, trazodone, or triazolam); hypersensitivity to saquinavir, ritonavir, or any component of these products; when administered with ritonavir, in patients with severe hepatic impairment.

Dosage and Administration

Adults and Children (16 y of age and older)

PO 1,000 mg twice daily with ritonavir 100 mg twice daily.

General Advice

  • Administer simultaneously with ritonavir. When administered with lopinavir 400 mg/ritonavir 100 mg twice daily, no additional ritonavir is needed.
  • Administer within 2 h after a meal.
  • For serious or severe toxicities, interrupt dose until the etiology of the event is identified or the toxicity resolves.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Aripiprazole

Plasma concentrations and pharmacologic effects of aripiprazole may be increased. Consider reducing the aripiprazole dose by 50% when administered with saquinavir.

Azole antifungal agents (eg, fluconazole, itraconazole, ketoconazole)

Azole antifungals may inhibit the metabolism of saquinavir, resulting in an increase in plasma concentrations. Azole antifungal agent plasma concentrations may be elevated. Monitor the patient for toxicity and adjust the dose of either agent as needed. Dosages of ketoconazole or itraconazole of more than 200 mg/day are not recommended.

Bosentan

Bosentan plasma concentrations may be elevated. In patients receiving saquinavir/ritonavir for at least 10 days when bosentan is started, start bosentan at 62.5 mg once daily or every other day, based on tolerability. In patients receiving bosentan, discontinue bosentan at least 36 h before starting saquinavir/ritonavir. At least 10 days after initiation of saquinavir/ritonavir, resume bosentan at 62.5 mg once daily or every other day, based on tolerability.

Cabazitaxel

Cabazitaxel plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid concurrent use.

Carbamazepine

Saquinavir may be less effective because of decreased plasma concentrations. Carbamazepine plasma concentrations may be elevated, increasing the risk of toxicity (eg, neurotoxicity). Closely monitor carbamazepine plasma concentrations when starting, stopping, or changing the saquinavir dose. Adjust the carbamazepine dose as needed or consider alternative treatment for carbamazepine.

Clarithromycin

Saquinavir and clarithromycin plasma levels may be increased, while concentrations of the active metabolite, 14-OH clarithromycin, may be decreased. Clarithromycin dosage adjustment may be necessary in patients with renal impairment.

Colchicine

Do not give colchicine and saquinavir/ritonavir to patients with hepatic or renal impairment. For treatment of gout flares, coadminister colchicine 0.6 mg followed by 0.3 mg 1 h later. Do not repeat dose earlier than 3 days. For prophylaxis of gout flares, if the original colchicine regimen was colchicine 0.6 mg twice daily, adjust the dose to 0.3 mg once daily. If the original colchicine dose was 0.6 mg once daily, adjust the regimen to colchicine 0.3 mg every other day. For treatment of familial Mediterranean fever, coadminister colchicine at a maximum daily dosage of 0.3 mg twice daily.

Contraceptives, oral (eg, ethinyl estradiol)

Estrogen concentrations may be reduced; instruct patient to use alternative or additional contraceptive measures.

Delavirdine

Delavirdine may increase saquinavir plasma concentrations and pharmacologic effects, while saquinavir may decrease delavirdine plasma concentrations and pharmacologic effects. Monitor the patient. Saquinavir dosage reduction and delavirdine dosage increase may be needed.

Dexamethasone, phenobarbital, phenytoin

Saquinavir plasma concentrations may be reduced, decreasing the efficacy. Use with caution.

Digoxin

Digoxin plasma concentrations may be elevated. Monitor digoxin concentrations when starting or stopping saquinavir. Adjust the digoxin dose as needed.

Docetaxel

Docetaxel plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Avoid concurrent use. If coadministration cannot be avoided, consider reducing the docetaxel dose by 50% with close clinical and laboratory monitoring.

Drugs primarily metabolized by CYP3A4 (eg, benzodiazepines [ie, alprazolam, clorazepate, diazepam, flurazepam], buspirone, calcium channel blockers [ie, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, verapamil], cyclosporine, dasatinib, eplerenone, erlotinib, eszopiclone, everolimus, iloperidone, ixabepilone, lapatinib, maraviroc, nilotinib, quetiapine, rapamycin, silodosin, tacrolimus, tamsulosin, temsirolimus, tricyclic antidepressants [eg, amitriptyline, imipramine])

Plasma levels may be increased by saquinavir; monitor patient and/or therapeutic concentration. Adjust dose as needed. Saquinavir plasma concentrations may increase with concomitant cyclosporine use. Coadministration of eplerenone and ritonavir is contraindicated. Avoid coadministration with silodosin or tamsulosin.

Drugs that are highly dependent on CYP3A for Cl that have a narrow therapeutic index or that may result in a potentially serious adverse reaction because of the expected magnitude of an interaction (eg, alfuzosin, amiodarone, bepridil, cisapride, conivaptan, dihydroergotamine, ergonovine, ergotamine, flecainide, lidocaine [systemic], lovastatin, methylergonovine, midazolam [oral], pimozide, propafenone, quinidine, ranolazine, rifampin, simvastatin, tolvaptan, trazodone, triazolam)

Coadministration with saquinavir/ritonavir is contraindicated.

Efavirenz

Coadministration may decrease saquinavir and/or efavirenz plasma levels.

Eletriptan

Saquinavir may increase eletriptan plasma concentrations and pharmacologic effects. It is recommended that eletriptan not be given within 72 h of saquinavir.

Erythromycin

Plasma concentration of erythromycin may be increased by concurrent use of saquinavir. Avoid coadministration because elevated concentrations of erythromycin have been associated with an increased risk for sudden death from cardiac causes.

Fluoxetine

Fluoxetine and saquinavir plasma concentrations may be elevated. Serotonin syndrome has been reported. If adverse reactions occur, dosage adjustments of one or both drugs may be needed.

Fluticasone inhalation

Plasma levels may be elevated by saquinavir; coadministration is not recommended.

Food

Saquinavir bioavailability and/or plasma concentrations may be increased after a high-fat or high-calorie meal. The effect of food has been shown to persist for up to 2 h. Advise patients to take saquinavir within 2 h after a meal.

Garlic

Saquinavir plasma concentrations may be decreased. Do not use garlic capsules while taking saquinavir as the sole protease inhibitor.

Grapefruit

Saquinavir plasma concentrations may be elevated; avoid coadministration of saquinavir and grapefruit products.

HMG-CoA reductase inhibitors (ie, atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin)

Plasma levels may be elevated by saquinavir, increasing the risk of myopathy, including rhabdomyolysis. Pravastatin levels may be reduced. Coadministration of lovastatin or simvastatin is contraindicated. Give the lowest possible dose of atorvastatin or rosuvastatin. Pravastatin levels may be reduced, decreasing the efficacy. Closely monitor the response of the patient and adjust the pravastatin dose as needed.

Loperamide

Saquinavir plasma concentrations and clinical effect may be decreased, while loperamide concentrations may be elevated. If coadministration cannot be avoided, closely monitor the patient for a decrease in antiretroviral activity.

Methadone

Methadone plasma concentration may be reduced; methadone dosage adjustments may be needed. Use with caution. Additive effects on QT and/or PR interval prolongation may occur with saquinavir/ritonavir.

Muscarinic receptor antagonists (eg, darifenacin, fesoterodine, solifenacin, tolterodine)

Muscarinic receptor antagonist plasma concentrations may be increased by saquinavir. When saquinavir is coadministered, do not allow the dose of darifenacin to exceed 7.5 mg daily, the dose of fesoterodine to exceed 4 mg daily, the dose of solifenacin to exceed 5 mg daily, or the dose of tolterodine to exceed 2 mg daily.

NNRTIs (ie, efavirenz, nevirapine)

Efavirenz and saquinavir plasma concentrations may be reduced. Appropriate doses for the coadministration of efavirenz or nevirapine and saquinavir/ritonavir have not been established.

Opioid analgesics (eg, buprenorphine, fentanyl, oxycodone)

Concurrent use may increase opioid analgesic plasma concentrations and prolong the half-life, increasing the risk of adverse reactions (eg, respiratory depression). Closely monitor respiratory function during administration, and for a longer period than usual after stopping the opioid analgesic. If the opioid analgesic is administered continuously, reduce the opioid analgesic dose as needed.

Phosphodiesterase type 5 inhibitors (ie, sildenafil, tadalafil, vardenafil)

Concurrent use may increase the phosphodiesterase 5 inhibitor concentration, resulting in severe and potentially fatal hypotension.

For treatment of erectile dysfunction

Reduce the dose and increase the dosing interval of the phosphodiesterase 5 inhibitor. Use with caution and increase monitoring of adverse reactions. Do not exceed sildenafil 25 mg every 48 h, tadalafil 10 mg every 72 h, or vardenafil 2.5 mg every 72 h.

For treatment of pulmonary arterial hypertension

Coadministration of sildenafil and saquinavir/ritonavir is contraindicated. In patients receiving saquinavir/ritonavir for at least 1 wk, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Avoid tadalafil during initiation of saquinavir/ritonavir. Stop tadalafil at least 24 h prior to starting saquinavir/ritonavir. After at least 1 wk following the initiation of saquinavir/ritonavir, resume tadalafil at 20 mg once daily. Increase the dosage to 40 mg once daily based on tolerability.

Protease inhibitors (eg, atazanavir, indinavir, ritonavir)

Saquinavir plasma concentrations may be increased. Ritonavir levels may be decreased. No dosage adjustment recommendations are available with coadministration of saquinavir and atazanavir.

Proton pump inhibitors (eg, omeprazole)

Saquinavir plasma concentrations may be elevated. Proton pump inhibitor plasma concentrations may be decreased. Monitor for saquinavir toxicity. Adjust the saquinavir dose as needed.

QT-prolonging agents (eg, erythromycin, halofantrine, ibutilide, neuroleptic agents [eg, clozapine, haloperidol, mesoridazine, phenothiazines, thioridazine, ziprasidone], pentamidine, sotalol)

Coadminister these agents with caution. Additive effects on QT and/or PR interval prolongation may occur with saquinavir/ritonavir. Saquinavir is contraindicated with drugs that both increase saquinavir plasma concentrations and prolong the QT interval.

Rifabutin

Saquinavir plasma levels may be reduced, while rifabutin levels may be elevated.

Risperidone, romidepsin

Risperidone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions (eg, extrapyramidal symptoms, NMS). Avoid coadministration.

Salmeterol

Salmeterol plasma concentrations may be elevated, increasing the risk of CV adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Coadministration is not recommended.

St. John's wort

Possible loss of virologic activity, including resistance to saquinavir or the class of protease inhibitors. Coadministration is not recommended.

Thyroid hormones (eg, levothyroxine)

Thyroxine serum concentrations may be increased or decreased, resulting in hyperthyroidism or hypothyroidism. Closely monitor thyroid function status when saquinavir is started or stopped. Adjust the thyroid dose as needed.

Tipranavir/Ritonavir

Saquinavir plasma levels may be reduced; coadministration with saquinavir is not recommended.

Warfarin

Warfarin plasma levels may be altered; INR monitoring is recommended.

Adverse Reactions

Cardiovascular

Heart murmur, hypertension, hypotension, peripheral vasoconstriction, syncope, thrombophlebitis.

CNS

Fatigue (6%); abnormal coordination, anxiety, asthenia, confusion, convulsions, depression, dizziness, dysgeusia, headache, hypoasthesia, insomnia, intracranial hemorrhage leading to death, lethargy, libido disorder, paresthesia, peripheral neuropathy, psychotic disorder, sleep disorder, somnolence, suicide attempt, tremor, unconsciousness.

Dermatologic

Pruritus, rash (3%); dry lips/skin, eczema (2%); acne, alopecia, bullous dermatitis, drug eruption, erythema, increased sweating, papillomatosis, severe cutaneous reaction associated with increased LFT, Stevens-Johnson syndrome, urticaria.

EENT

Tinnitus, visual impairment.

GI

Nausea (11%); diarrhea (8%); vomiting (7%); abdominal pain (6%); constipation (2%); abdominal discomfort, anorexia, ascites, dry mouth, dyspepsia, dysphagia, eructation, flatulence, gastritis, GI hemorrhage, intestinal obstruction, mucosa ulceration, pancreatitis.

Genitourinary

Nephrolithiasis.

Hematologic-Lymphatic

Acute myeloid leukemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia.

Hepatic

Chronic active hepatitis, hepatitis, hepatomegaly, hyperbilirubinemia, jaundice, portal hypertension.

Lab Tests

Increased alkaline phosphatase, ALT, amylase, AST, CPK, GGT, and LDH.

Metabolic-Nutritional

Lipodystrophy (5%); diabetes mellitus/hyperglycemia (3%); appetite increase, appetite decrease, dehydration, hypertriglyceridemia, increased weight, redistribution/accumulation of body fat.

Musculoskeletal

Back pain (2%); arthralgia, muscle spasms, myalgia, polyarthritis.

Respiratory

Pneumonia (5%); bronchitis, sinusitis (3%); cough, dyspnea.

Miscellaneous

Fever, influenza (3%); allergic reaction, chest pain, edema, lymphadenopathy, wasting syndrome.

Precautions

Monitor

Perform clinical chemistry, viral load, and CD4 count prior to therapy and at appropriate intervals thereafter. Monitor cholesterol and triglyceride levels prior to initiation and periodically during therapy. Monitor potassium and magnesium prior to starting therapy and periodically thereafter. Monitor ECG prior to initiation of treatment. Perform ECG monitoring in patients with CHF, bradyarrhythmias, hepatic impairment, structural heart disease, electrolyte abnormalities, preexisting conduction abnormalities, cardiomyopathies, and/or ischemic heart disease.


Pregnancy

Category B .

Lactation

Undetermined. HIV-infected mothers should not breast-feed infants.

Children

Safety and efficacy not established for children younger than 16 y of age.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Renal Function

Use with caution in patients with severe renal impairment or ESRD.

Hepatic Function

Worsening of liver disease has been reported in patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism, and/or underlying liver abnormalities. Contraindicated in patients with severe hepatic impairment when used in combination with ritonavir.

Concomitant therapy

Saquinavir must be used in combination with ritonavir.

Diabetes/Hyperglycemia

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported.

Fat distribution

Accumulation or redistribution of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, has occurred in patients receiving antiretroviral therapy. A causal relationship has not been established.

Hemophilia

Spontaneous bleeding has been reported in patients with hemophilia A and B; however, a causal relationship has not been established.

Hyperlipidemia

Elevated cholesterol and/or triglyceride levels have been reported.

Immune reconstitution syndrome

During initial phase of treatment, patients may develop an inflammatory response to indolent or residual opportunistic infections.

Lactose intolerance

Each capsule contains lactose (anhydrous) 63.3 mg. This amount should not induce intolerance symptoms.

PR interval prolongation

May occur. Patients with underlying structural heart disease, preexisting conduction abnormalities, cardiomyopathies, and ischemic heart disease may be at increased risk for developing cardiac conduction abnormalities.

QT interval prolongation

May occur. Avoid in patients with long QT syndrome.

Resistance/Cross-resistance

Varying degrees of cross-resistance have been observed among protease inhibitors. Continued administration following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

Toxicity

If serious or severe toxicity occurs during treatment, interrupt therapy until the etiology of the event is determined or the toxicity resolves.

Overdosage

Symptoms

No serious toxicities reported.

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Advise patient of the importance of taking the product within 2 h after a meal.
  • Advise patient that ritonavir must be taken at the same time as saquinavir.
  • Warn patient not to change the dose or discontinue medication without consulting health care provider.
  • Inform patient that this medication is not a cure for HIV infection and that secondary illnesses associated with the disease may continue to be acquired.
  • Emphasize to patient, family, and significant others that this medication does not reduce the risk of transmitting HIV to others through sexual contact or blood contamination.
  • Inform patient to report any serious adverse reactions to health care provider.
  • Explain that the medication may affect heart rhythm and electrical activity in the heart. Advise patient that it is important to report any symptoms, such as dizziness, fainting, light-headedness, or sensation of abnormal heartbeats, immediately.
  • Explain that the long-term effects of this medication are not known, and that the initial results have not demonstrated a reduction in symptoms or prolongation of life.
  • Advise patient that saquinavir is recommended for use in combination with active antiretroviral therapy and that adherence to the prescribed regimen is strongly recommended.
  • Inform patient that redistribution or accumulation of body fat may occur, and that long-term health effects are not known.

Copyright © 2009 Wolters Kluwer Health.

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