(SEE PRECAUTIONS)

INVIRASE must be used in combination with ritonavir, which significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels.

Concomitant Therapy with Ritonavir Adverse Reactions

In combination with ritonavir the recommended dose of INVIRASE is 1000 mg two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents. Table 7 lists grade 2, 3 and 4 related adverse events that occurred in ≥ 2% of patients receiving saquinavir soft gel capsules with ritonavir (1000/100 mg bid).

Table 7 Grade 2, 3 and 4 Related Adverse Events (All Causality) Reported in ≥ 2% of Adult Patients in the MaxCmin 1 Study of saquinavir soft gel capsules in Combination with Ritonavir 1000/100 mg bid

Limited experience is available from three studies investigating the pharmacokinetics of the INVIRASE 500 mg film-coated tablet compared to the INVIRASE 200 mg capsule in healthy volunteers (n=140). In two of these studies saquinavir was boosted with ritonavir; in the other study, saquinavir was administered as single drug. The INVIRASE tablet and the capsule formulations were similarly tolerated. The most common adverse events were gastrointestinal disorders (such as diarrhea). Similar bioavailability was demonstrated and no clinically significant differences in saquinavir exposures were seen. Thus, similar safety profiles are expected between the two INVIRASE formulations.

In a study investigating the drug-drug interaction of rifampin 600 mg/day daily and INVIRASE 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted INVIRASE) involving 28 healthy volunteers, 11 of 17 healthy volunteers (65%) exposed concomitantly to rifampin and ritonavir-boosted INVIRASE developed severe hepatocellular toxicity presented as increased hepatic transaminases. In some subjects, transaminases increased up to > 20-fold the upper limit of normal and were associated with gastrointestinal symptoms, including abdominal pain, gastritis, nausea, and vomiting. Following discontinuation of all three drugs, clinical symptoms abated and the increased hepatic transaminases normalized (see CONTRAINDICATIONS).

Additional Adverse Reactions Reported with Saquinavir

Additionally, adverse experiences of any intensity, at least remotely related to saquinavir, that were reported from clinical trials using INVIRASE or saquinavir soft gel capsules with or without ritonavir, are listed below by body system:

Body as a Whole: allergic reaction, anorexia, asthenia, chest pain, drug fever, edema, fatigue, fever, intoxication, mucosa damage, parasites external, retrosternal pain, shivering, wasting syndrome, weakness generalized, weight decrease, redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution)

Cardiovascular: cyanosis, heart murmur, heart valve disorder, hypertension, hypotension, peripheral vasoconstriction, syncope, thrombophlebitis, vein distended

Endocrine/Metabolic: appetite decrease, appetite disturbance, dehydration, diabetes mellitus, dry eye syndrome, hypercalcemia, hyperglycemia, hyperkalemia, hypernatremia, hyperphosphatemia, hypertriglyceridemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia, weight increase, xerophthalmia

Gastrointestinal: ascites, abdominal discomfort, buccal mucosa ulceration, cheilitis, colic abdominal, constipation, dyspepsia, dysphagia, esophagitis, eructation, exacerbation of chronic liver disease with grade 4 LFT, feces bloodstained, feces discolored, flatulence, gastralgia, gastritis, gastrointestinal inflammation, intestinal obstruction, gingivitis, glossitis, hemorrhage rectum, hemorrhoids, hepatitis, hepatomegaly, hepatosplenomegaly, hyperbilirubinemia, infectious diarrhea, jaundice, liver enzyme disorder, melena, pain pelvic, painful defecation, pancreatitis, parotid disorder, portal hypertension, right and left upper quadrant abdominal pain, salivary glands disorder, stomach upset, stomatitis, toothache, tooth disorder, vomiting

Hematologic: anemia, bleeding dermal, hemolytic anemia, leucopenia, microhemorrhages, neutropenia, pancytopenia, splenomegaly, thrombocytopenia, thrombocytopenia leading to death

Investigations: ALT increase, AST increase, GGT increase, increased alkaline phosphatase, increased creatine phosphokinase, increased gamma GT, isolated increase in transaminase, raised amylase, raised LDH, TSH increase

Musculoskeletal: arthralgia, arthritis, back pain, cramps leg, cramps muscle, creatine phosphokinase increased, musculoskeletal disorders, musculoskeletal pain, myalgia, stiffness, tissue changes, trauma

Neoplasms benign, malignant and unspecified: acute myeloblastic leukemia

Neurological: ataxia, bowel movements frequent, confusion, convulsions, dizziness, dysarthria, dysesthesia, extremity numbness, headache, heart rate disorder, hyperesthesia, hyperreflexia, hyporeflexia, light-headed feeling, mouth dry, myelopolyradiculoneuritis, numbness face, pain facial, paresis, paresthesia, peripheral neuropathy, poliomyelitis, prickly sensation, progressive multifocal leukoencephalopathy, seizures, spasms, tremor, unconsciousness

Psychological: agitation, amnesia, anxiety, anxiety attack, depression, dreaming excessive, euphoria, hallucination, insomnia, intellectual ability reduced, irritability, lethargy, libido disorder, overdose effect, psychic disorder, psychosis, somnolence, speech disorder, suicide attempt

Reproductive System: impotence, prostate enlarged, vaginal discharge

Resistance Mechanism: abscess, angina tonsillaris, candidiasis, cellulitis, herpes simplex, herpes zoster, infection bacterial, infection mycotic, infection staphylococcal, influenza, lymphadenopathy, moniliasis, tumor

Respiratory: bronchitis, cough, dyspnea, epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary disease, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection

Skin and Appendages: acne, alopecia, bullous skin eruption and polyarthritis, chalazion, dermatitis, dermatitis seborrheic, eczema, erythema, folliculitis, furunculosis, hair changes, hot flushes, nail disorder, night sweats, papillomatosis, photosensitivity reaction, pigment changes skin, rash maculopapular, severe cutaneous reaction associated with increased liver function tests, skin disorder, skin nodule, skin ulceration, Stevens-Johnson syndrome, sweating increased, urticaria, verruca, xeroderma

Special Senses: blepharitis, earache, ear pressure, eye irritation, hearing decreased, otitis, taste alteration, tinnitus, visual disturbance

Urinary System: micturition disorder, nephrolithiasis, renal calculus, urinary tract bleeding, urinary tract infection

Postmarketing Experience with INVIRASE

Additional adverse events that have been observed during the postmarketing period are similar to those seen in clinical trials with INVIRASE and saquinavir soft gel capsules alone or in combination with ritonavir.

Several drug interaction studies have been completed with both INVIRASE and saquinavir soft gel capsules. Observations from drug interaction studies with saquinavir soft gel capsules may not be predictive for INVIRASE. Because ritonavir is coadministered, prescribers should also refer to the prescribing information for ritonavir regarding drug interactions associated with this agent.

The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-Glycoprotein (Pgp). Therefore, drugs that affect CYP3A4 and/or Pgp, may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other drugs that are substrates for CYP3A4 or Pgp.

Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in Table 4 under CONTRAINDICATIONS. Additional drugs that are not recommended for coadministration with INVIRASE and ritonavir are included in Table 5. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in Table 2, which summarizes the effect of saquinavir, administered as saquinavir soft gel capsules or INVIRASE, on the geometric mean AUC and Cmax of coadministered drugs and Table 3, which summarizes the effect of coadministered drugs on the geometric mean AUC and Cmax of saquinavir. Clinical dose recommendations can be found in Table 6. The magnitude of the interactions may be different when INVIRASE is given with ritonavir.

When coadministering INVIRASE/ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased concentrations. Examples and clinical dose recommendations can be found in Table 6.

Table 5 Drugs That Should Not Be Coadministered With INVIRASE/Ritonavir

Table 6 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction (Information in the table applies to INVIRASE/ritonavir)

Drugs That Are Mainly Metabolized by CYP3A4

Although specific studies have not been performed, coadministration with drugs that are mainly metabolized by CYP3A4 (eg, calcium channel blockers, dapsone, disopyramide, quinine, amiodarone, quinidine, warfarin, tacrolimus, cyclosporine, ergot derivatives, pimozide, carbamazepine, fentanyl, alfentanyl, alprazolam, and triazolam) may have elevated plasma concentrations when coadministered with saquinavir; therefore, these combinations should be used with caution. Since INVIRASE is coadministered with ritonavir, the ritonavir label should be reviewed for additional drugs that should not be coadministered.

Inducers of CYP3A4

Coadministration with compounds that are potent inducers of CYP3A4 (eg, phenobarbital, phenytoin, dexamethasone, carbamazepine) may result in decreased plasma levels of saquinavir.

Rifampin

In a Phase I, randomized, open-label, multiple-dose study involving 28 healthy volunteers, 11 of 17 (65%) healthy volunteers exposed concomitantly to rifampin 600 mg once daily and INVIRASE 1000 mg/ritonavir 100 mg given twice daily (ritonavir-boosted INVIRASE) developed severe hepatocellular toxicity during the 28-day study period. Therefore, rifampin should not be administered concomitantly in patients taking ritonavir-boosted INVIRASE as part of an ART regimen (see CONTRAINDICATIONS).

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