Saquinavir adverse reactions

# Adverse Reactions
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 saquinavir 600 mg alone or in combination with ZDV or ddC. Combination dosing with ritonavir is based on 352 HIV-1 infected subjects and 166 healthy subjects who received various combinations of either saquinavir (hard gel or soft-gel capsules) with ritonavir.
The recommended dose of INVIRASE is 1000 mg twice daily co-administered with ritonavir 100 mg twice daily, in combination with other antiretroviral agents. Table 2 lists grade 2, 3 and 4 adverse events that occurred in 2% of subjects receiving saquinavir soft gel capsules with ritonavir (1000/100 mg bid).
Limited experience is available from three trials 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 trials saquinavir was boosted with ritonavir; in the other trial, 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 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 healthy volunteers (65%) exposed concomitantly to rifampin and ritonavir-boosted INVIRASE 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 the increased 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 (incl cysts and polyps)
Acute myeloid leukemia, papillomatosis

### Nervous system disorders
Confusion, convulsions, coordination abnormal, dizziness, dysgeusia, headache, hypoaesthesia, 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 hard gel capsules (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 (INVIRASE + 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 (INVIRASE + 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 and saquinavir soft gel capsules 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, torsades de pointes has been reported rarely .