Saquinavir Mesylate

Trade Names:
Invirase
- Capsules 200 mg (as mesylate)
- Tablets 500 mg (as mesylate)

Pharmacology

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

Pharmacokinetics

Absorption

Bioavailability averaged 4%.

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).

Special Populations

Approximately 1% is excreted via urine. Impact of renal function impairment on elimination should be minimal.

Pharmacokinetics have not been studied in patients with hepatic function impairment.

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

Exposure is higher in women than in men (mean increases in AUC and C _max are 56% and 26%, respectively).

Indications and Usage

Treatment of HIV infection in combination with ritonavir and other antiretroviral agents.

Contraindications

Coadministration of amiodarone, bepridil, cisapride, ergot derivatives, flecainide, midazolam, pimozide, propafenone, quinidine, rifampin, or triazolam; hypersensitivity to saquinavir or any component of the product; when administered with ritonavir, in patients with severe hepatic function impairment.

Dosage and Administration

PO 1,000 mg twice daily.

General Advice

• Administer product simultaneously with ritonavir 100 mg twice daily.
• Administer product within 2 h after a meal.

Storage/Stability

Store at 59° to 86°F. Store in tightly closed bottle.

Drug Interactions

Saquinavir plasma levels may be elevated, increasing the risk of adverse reactions.

Saquinavir plasma levels may be elevated; however, appropriate dose when coadministered with saquinavir/ritonavir has not been established.

Saquinavir and clarithromycin plasma levels may be increased; clarithromycin dosage adjustment may be necessary in patients with renal function impairment.

Coadministration with saquinavir/ritonavir is contraindicated.

Digoxin plasma concentrations may be elevated. Use with caution.

Plasma levels may be increased by saquinavir; monitor patient and/or therapeutic concentration. Adjust dose as needed.

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

Saquinavir plasma concentrations may be decreased.

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

Plasma levels may be elevated by saquinavir, increasing the risk of myopathy, including rhabdomyolysis. Coadministration of lovastatin or simvastatin is not recommended. Give the lowest possible dose of atorvastatin or rosuvastatin.

Estrogen concentrations may be reduced; alternative or additional contraceptive measures should be used.

Ritonavir plasma levels may be reduced.

Methadone plasma concentration may be reduced; methadone dosage adjustments may be needed.

Efavirenz and saquinavir plasma concentrations may be reduced; however, appropriate dose when coadministered with saquinavir/ritonavir has not been established.

Plasma concentrations may be elevated by saquinavir. Monitor for adverse reactions when administered with saquinavir/ritonavir. Use with caution and at dosages not exceeding: sildenafil 25 mg every 48 h, tadalafil 10 mg every 72 h, or vardenafil 2.5 mg every 72 h.

Saquinavir plasma concentrations may be reduced, decreasing the efficacy.

Saquinavir plasma concentrations may be increased; however, appropriate dose when coadministered with saquinavir and/or ritonavir has not been established. Nelfinavir plasma concentrations may be increased.

Saquinavir plasma levels may be reduced, while rifabutin levels may be elevated; however, appropriate dose adjustments have not been established.

Possible loss of virologic activity, including resistance to saquinavir or the class of protease inhibitors.

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

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

Laboratory Test Interactions

None well documented.

Adverse Reactions

The following adverse reactions were reported with saquinavir monotherapy or in combination with ritonavir.

Cardiovascular

Cyanosis, distended vein, heart murmur, heart rate disorder, heart valve disorder, hypertension, hypotension, peripheral vasoconstriction, syncope, thrombophlebitis.

CNS

Fatigue (6%); agitation, amnesia, anxiety, anxiety attack, appetite disturbance, asthenia, ataxia, confusion, convulsions, decreased appetite, depression, dizziness, excessive dreaming, dysarthria, dysesthesia, euphoria, extremity numbness, facial numbness, facial pain, hallucination, headache, hyperesthesia, hyperreflexia, hyporeflexia, insomnia, irritability, lethargy, libido disorder, light-headed feeling, myelopolyradiculoneuritis, overdose effect, paresis, paresthesia, peripheral neuropathy, poliomyelitis, prickly sensation, progressive multifocal leukoencephalopathy, psychic disorder, psychosis, reduced intellectual ability, seizures, somnolence, spasms, speech disorder, suicide attempt, tremor, unconsciousness, weakness.

Dermatologic

Pruritus, rash (3%); dry lips/skin, eczema (2%); acne, alopecia, bullous skin eruption, chalazion, dermatitis, erythema, folliculitis, furunculosis, hair changes, hot flashes, increased sweating, maculopapular rash, nail disorder, night sweats, papillomatosis, photosensitivity, pigment changes, seborrheic dermatitis, severe cutaneous reaction associated with increased LFT, skin disorder, skin nodule, skin ulceration, Stevens-Johnson syndrome, urticaria, verruca, xeroderma.

EENT

Blepharitis, decreased hearing, dry eye syndrome, earache, ear pressure, epistaxis, eye irritation, laryngitis, otitis, pharyngitis, rhinitis, taste alteration, tinnitus, visual disturbance, xerophthalmia.

GI

Nausea (11%); diarrhea (8%); vomiting (7%); abdominal pain (6%); constipation (2%); abdominal discomfort, anorexia, ascites, bloodstained feces, buccal mucosa ulceration, cheilitis, colic, discolored feces, dry mouth, dyspepsia, dysphagia, esophagitis, eructation, flatulence, frequent bowel movements, gastralgia, gastritis, GI inflammation, intestinal obstruction, gingivitis, glossitis, hemorrhoids, infectious diarrhea, melena, pelvic pain, painful defecation, pancreatitis, parotid disorder, rectal hemorrhage, right and left quadrant abdominal pain, salivary gland disorder, stomatitis, toothache, tooth disorder, upset stomach.

Genitourinary

Enlarged prostate, impotence, micturition disorder, nephrolithiasis, renal calculus, urinary tract bleeding, UTI, vaginal discharge.

Hematologic-Lymphatic

Acute myeloblastic leukemia, anemia, dermal bleeding, hemolytic anemia, leucopenia, lymphadenopathy, microhemorrhages, neutropenia, pancytopenia, splenomegaly, thrombocytopenia, thrombocytopenia leading to death.

Hepatic

Exacerbation of chronic liver disease with grade 4 LFT, hepatitis, hepatomegaly, hepatosplenomegaly, hyperbilirubinemia, jaundice, liver enzyme disorder, portal hypertension.

Lab Tests

Increased alkaline phosphatase, ALT, amylase, AST, creatine phosphokinase, gamma-glutamyl transferase, LDH, and TSH.

Metabolic-Nutritional

Lipodystrophy (5%); diabetes mellitus/hyperglycemia (3%); decreased weight, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hypernatremia, hyperphosphatemia, hypertriglyceridemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia, increased weight, redistribution/accumulation of body fat.

Musculoskeletal

Back pain (2%); arthralgia, arthritis, leg cramps, muscle cramps, musculoskeletal disorders, musculoskeletal pain, myalgia, polyarthritis, stiffness, tissue changes, trauma.

Respiratory

Pneumonia (5%); bronchitis, sinusitis (3%); cough, dyspnea, hemoptysis, pulmonary disease, respiratory disorder, upper respiratory tract infection.

Miscellaneous

Fever, influenza (3%); abscess, allergic reaction, angina tonsillaris, bacterial infection, candidiasis, cellulitis, chest pain, drug fever, edema, external parasites, herpes simplex, herpes zoster, intoxication, lymphadenopathy, moniliasis, mucosa damage, mycotic infection, retrosternal pain, shivering, staphylococcal infection, tumor, wasting syndrome.

Precautions

Pregnancy

Category B .

Lactation

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

Children

Not recommended for children younger than 16 yr of age.

Elderly

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

Renal Function

Because only 1% is excreted in the urine, the effect of renal function impairment is expected to be minimal.

Hepatic Function

Exercise caution when administering to patients with hepatic function impairment.

Photosensitivity

May occur; advise patients to take protective measures against exposure to UV light or sunlight until tolerance is determined.

Diabetes

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

Dosage adjustment

Do not reduce dose; lower doses do not exhibit antiviral activity.

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.

Hepatic effects

Worsening of liver disease has been reported in patients with chronic alcoholism, hepatitis B or C, and/or underlying liver abnormalities.

Hyperlipidemia

Elevated cholesterol and/or triglyceride levels have been reported. Markedly elevated triglyceride levels are risk factors for pancreatitis.

Immune reconstitution syndrome

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

Nucleoside analog therapy

Saquinavir must be used in combination with nucleoside analog (eg, zalcitabine, zidovudine) therapy.

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.

Overdosage

Symptoms

No acute toxicities or sequelae have been reported.

Patient Information

• Advise patient regarding importance of taking the product within 2 h after a meal.
• Warn patient not to change the dose or discontinue medication without consulting health care provider.
• Explain that patient will be required to have frequent follow-up blood and urine tests during the course of treatment and to keep appointments.
• Inform patient that this medication is not a cure for HIV infection and 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 long-term effects of this medication are not known, and the initial results have not demonstrated a reduction in symptoms or prolongation of life.
• Caution patient regarding possibility of photosensitivity and advise use of protective measures (eg, use sunscreen) until tolerance is determined.
• Advise patient that saquinavir is recommended for use in combination with active antiretroviral therapy and 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.

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