INVIRASE SIDE EFFECTS

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• PR Interval Prolongation
• QT Interval Prolongation

Clinical Trial Experience In Adult Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The original INVIRASE safety database consisted of a total of 574 adult subjects who received 600 mg of saquinavir mesylate capsules (hard gel) alone or in combination with zidovudine (ZDV) or zalcitabine (ddC). Combination dosing with ritonavir is based on 352 HIV-1 infected subjects and 166 healthy subjects who received various combinations of either saquinavir mesylate capsules (hard gel or soft gel) with ritonavir.

The recommended dose of INVIRASE is 1,000 mg twice daily co-administered with ritonavir 100 mg twice daily. Table 1 lists Grade 2, 3 and 4 adverse events that occurred in ≥2% of subjects receiving saquinavir mesylate capsules (soft gel) with ritonavir (1000/100 mg bid).

Table 1 Grade 2, 3 and 4 Adverse Events (All Causality^a) Reported in ≥2% of Adult Subjects in the MaxCmin 1 Study of Saquinavir Mesylate Capsules (soft gel) in Combination with Ritonavir 1000/100 mg Twice a Day

Limited experience is available from three trials investigating the pharmacokinetics of the INVIRASE 500-mg film-coated tablet compared to the 200-mg saquinavir mesylate capsules (hard gel) in healthy volunteers (n=140). In two of these trials, saquinavir was combined with ritonavir; in the other trial, saquinavir was administered as single drug. The INVIRASE tablet and the saquinavir mesylate capsule (hard gel) were similarly tolerated. The most common adverse events were gastrointestinal disorders (nausea, vomiting, and 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.

A study investigating the drug-drug interaction of rifampin 600 mg/day daily and INVIRASE 1000 mg/ritonavir 100 mg twice daily enrolled 28 healthy volunteers. Eleven of 17 (65%) healthy volunteers exposed concomitantly to rifampin and INVIRASE/ritonavir developed severe hepatocellular toxicity which 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 hepatic transaminases normalized.

Additional Adverse Reactions Reported During Clinical Trials with Saquinavir

Blood and lymphatic system disorders: anemia, hemolytic anemia, leukopenia, lymphadenopathy, neutropenia, pancytopenia, thrombocytopenia

Cardiac disorders: heart murmur, syncope

Ear and labyrinth disorders: tinnitus

Eye disorders: visual impairment

Gastrointestinal disorders: abdominal discomfort, ascites, dyspepsia, dysphagia, eructation, flatulence, gastritis, gastrointestinal hemorrhage, intestinal obstruction, mouth dry, mucosal ulceration, pancreatitis

General disorders and administration site conditions: anorexia, asthenia, chest pain, edema, lethargy, wasting syndrome, weight increased

Hepatobiliary disorders: chronic active hepatitis, hepatitis, hepatomegaly, hyperbilirubinemia, jaundice, portal hypertension

Immune system disorders: allergic reaction

Investigations: ALT increase, AST increase, blood creatine phosphokinase increased, increased alkaline phosphatase, GGT increase, raised amylase, raised LDH

Metabolism and nutrition disorders: increased or decreased appetite, dehydration, hypertriglyceridemia

Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms, myalgia, polyarthritis

Neoplasms benign, malignant and unspecified (including cysts and polyps): acute myeloid leukemia, papillomatosis

Nervous system disorders: confusion, convulsions, coordination abnormal, dizziness, dysgeusia, headache, hypoesthesia, intracranial hemorrhage leading to death, loss of consciousness, paresthesia, peripheral neuropathy, somnolence, tremor

Psychiatric disorders: anxiety, depression, insomnia, libido disorder, psychotic disorder, sleep disorder, suicide attempt

Renal and urinary disorders: nephrolithiasis

Respiratory, thoracic and mediastinal disorders: cough, dyspnea

Skin and subcutaneous tissue disorders: acne, alopecia, dermatitis bullous, drug eruption, erythema, severe cutaneous reaction associated with increased liver function tests, Stevens-Johnson syndrome, sweating increased, urticaria

Vascular disorders: hypertension, hypotension, thrombophlebitis, peripheral vasoconstriction

Clinical Trial Experience In Pediatric Subjects

Limited safety data are available from two pediatric clinical trials of saquinavir mesylate capsules (hard gel) (approximately 50 mg per kg twice daily) used in combination with either low dose ritonavir or lopinavir/ritonavir. These trials enrolled pediatric subjects aged 4 months to 16 years old. In the HIVNAT 017 study (saquinavir mesylate capsules (hard gel) + lopinavir/ritonavir), adverse events were reported in 90% of the 50 subjects enrolled. The most commonly reported adverse events considered related to study treatment were diarrhea (18%) and vomiting (10%). In the NV20911 study (saquinavir mesylate capsules (hard gel) + ritonavir), 4 subjects (22% of 18 enrolled) experienced adverse events that were considered related to INVIRASE + ritonavir. These events (n) were vomiting (3), abdominal pain (1) and diarrhea (1). All reported adverse events were mild or moderate in intensity. The adverse reaction profile of INVIRASE in the pediatric trials is similar to that observed in adult trials.

Postmarketing Experience

Additional adverse events identified during postmarketing use are similar to those observed in clinical trials with INVIRASE, saquinavir mesylate capsules (hard gel and soft gel) alone or in combination with ritonavir. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to INVIRASE exposure. In addition, torsade de pointes has been reported rarely.

SRC: NLM .