Invirase Side Effects

Please note - some side effects for Invirase may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Invirase - for the Consumer

Invirase

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Invirase:

Anxiety; blurred vision; body fat changes; changes in sexual desire; constipation; diarrhea; dizziness; dry lips or skin; gas; headache; heartburn; mouth sores; nausea; night sweats; sleeplessness; stomach discomfort; taste changes; tenderness or bleeding of the gums; tiredness; vomiting; warts; weight gain.

Seek medical attention right away if any of these SEVERE side effects occur when using Invirase:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); back pain; blood in the vomit or stools; chest tightness or pain; confusion; coughing up blood; dark urine; depression or thoughts of suicide; difficulty urinating; excessive thirst, hunger, or urination; fainting; fast, slow, or irregular heartbeat; fever; flu-like symptoms; itching; loss of appetite; loss of coordination; numbness or tingling; pain in muscles or joints; pale stools; reddened, blistered, or swollen skin; seizures; severe or persistent cough; severe or persistent dizziness or lightheadedness; shortness of breath; stomach pain or tenderness; unusual bruising or bleeding; unusual vaginal discharge or odor; unusual weakness; white patches in the mouth; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Invirase Side Effects - for the Professional

Invirase

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

• PR Interval Prolongation [see Warnings and Precautions (5.2)]
• QT Interval Prolongation [see Warnings and Precautions (5.3)]

Clinical Trials Experience

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 patients who received saquinavir 600 mg alone or in combination with ZDV or ddC. Combination dosing with ritonavir is based on 352 HIV-1 infected patients 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 patients receiving saquinavir soft gel capsules with ritonavir (1000/100 mg bid).

Table 2 Grade 2, 3 and 4 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

Adverse Events	Saquinavir soft gel capsules 1000 mg plus Ritonavir 100 mg bid (48 weeks) N=148 n (%=n/N)
* Includes events with unknown relationship to study drug
Endocrine Disorders
Diabetes mellitus/hyperglycemia	4 (2.7)
Lipodystrophy	8 (5.4)
Gastrointestinal Disorders
Nausea	16 (10.8)
Vomiting	11 (7.4)
Diarrhea	12 (8.1)
Abdominal Pain	9 (6.1)
Constipation	3 (2.0)
General Disorders and Administration Site Conditions
Fatigue	9 (6.1)
Fever	5 (3.4)
Musculoskeletal Disorders
Back Pain	3 (2.0)
Respiratory Disorders
Pneumonia	8 (5.4)
Bronchitis	4 (2.7)
Influenza	4 (2.7)
Sinusitis	4 (2.7)
Dermatological Disorders
Rash	5 (3.4)
Pruritus	5 (3.4)
Dry lips/skin	3 (2.0)
Eczema	3 (2.0)

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 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 [see Contraindications (4)].

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

Postmarketing Experience

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. 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.

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Side Effects by Body System - for Healthcare Professionals

General

Gastrointestinal disorders (such as diarrhea) have been reported the most frequently. Additional side effects have been reported during postmarketing experience that are similar to those observed in clinical trials with saquinavir mesylate and saquinavir soft gel capsules alone or in combination with ritonavir.

Gastrointestinal

Gastrointestinal side effects have included nausea (10.8%), diarrhea (8.1%), vomiting (7.4%), abdominal pain (6.1%), and constipation (2%) during a trial with saquinavir soft gel capsules in combination with ritonavir. Other gastrointestinal side effects have included abdominal discomfort, anorexia, dyspepsia, dysphagia, eructation, flatulence, gastritis, gastrointestinal hemorrhage, intestinal obstruction, dry mouth, mucosal ulceration, and pancreatitis. Decreased appetite, cheilitis, abdominal colic, constipation, esophageal ulceration, esophagitis, frequent bowel movements, discolored and bloodstained feces, gastralgia, gastroesophageal reflux, gastrointestinal inflammation, gingivitis, gastrointestinal ulcer, glossitis, hemorrhoids, infectious diarrhea, melena, painful defecation, parotid disorder, right and left upper quadrant abdominal pain, pruritus ani, pyrosis, rectal hemorrhage, salivary gland disorder, stomach upset, stomatitis, taste alteration, toothache, and tooth disorder have been reported.

Other

Other side effects have included fatigue (6.1%) and fever (3.4%) during a trial with saquinavir soft gel capsules in combination with ritonavir. Ascites, asthenia, chest pain, edema, lethargy, wasting syndrome, intoxication, mucosa damage, external parasites, retrosternal pain, shivering, generalized weakness, earache, ear pressure, and otitis have been reported.

Metabolic

Metabolic side effects have included lipodystrophy (5.4%) and diabetes mellitus/hyperglycemia (2.7%) during a trial with saquinavir soft gel capsules in combination with ritonavir. Dehydration, increased or decreased appetite, hypertriglyceridemia, increased weight, raised amylase, increased alkaline phosphatase, raised LDH, hypoglycemia, hypercalcemia, hypocalcemia, hyperphosphatemia, hypophosphatemia, hyperkalemia, hypokalemia, hypernatremia, hyponatremia, hyperlipidemia, and weight decrease have been reported. Elevated cholesterol and/or triglyceride levels have been reported with saquinavir in combination with ritonavir. Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement, peripheral wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving protease inhibitors. New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing experience in patients receiving protease inhibitors.

During postmarketing surveillance, the average time to onset of hyperglycemia and diabetes was 76 days; however, some events occurred as early as 4 days after the initiation of therapy.

The mechanism and long-term consequences of body fat redistribution/accumulation are currently unknown and a causal relationship has not been established.

Respiratory

Respiratory side effects have included pneumonia (5.4%), bronchitis (2.7%), influenza (2.7%), and sinusitis (2.7%) during a trial with saquinavir soft gel capsules in combination with ritonavir. Cough, dyspnea, epistaxis, hemoptysis, laryngitis, pharyngitis, pulmonary disease, respiratory disorder, rhinitis, and upper respiratory tract infection have been reported.

Dermatologic

Dermatologic side effects have included rash (3.4%), pruritus (3.4%), dry lips/skin (2%), and eczema (2%) during a trial with saquinavir soft gel capsules in combination with ritonavir. Acne, alopecia, bullous dermatitis, drug eruption, erythema, severe cutaneous reaction associated with increased liver function tests, Stevens-Johnson syndrome, increased sweating, urticaria, dermatitis, exanthema, folliculitis, furunculosis, hair changes, hot flushes, maculopapular rash, nail disorders, night sweats, photosensitivity reaction, psoriasis, seborrheic dermatitis, skin disorder, skin nodule, skin pigment changes, skin ulceration, verruca, and xeroderma have been reported.

Musculoskeletal

Musculoskeletal side effects have included back pain (2%) during a trial with saquinavir soft gel capsules in combination with ritonavir. Arthralgia, muscle spasms, myalgia, polyarthritis, elevated blood creatine phosphokinase, arthritis, leg cramps, muscle cramps, musculoskeletal pain, musculoskeletal disorders, stiffness, tissue changes, and trauma have been reported.

Cardiovascular

Cardiovascular side effects have included QT interval prolongation, PR interval prolongation, heart murmur, hypertension, hypotension, thrombophlebitis, and peripheral vasoconstriction. Cyanosis, heart rate disorder, heart valve disorder, stroke, and vein distension have also been reported. Cases of second or third degree atrioventricular block have been reported rarely. Torsades de pointes has been reported rarely during postmarketing experience.

Saquinavir plus ritonavir show a dose-dependent prolongation of the QT and PR intervals.

Hematologic

Hematologic side effects have included anemia, hemolytic anemia, leukopenia, lymphadenopathy, neutropenia, pancytopenia, and thrombocytopenia. Splenomegaly, dermal bleeding, and microhemorrhages have also been reported. Spontaneous bleeding in patients with hemophilia A and B has been associated with protease inhibitors. In many of the reported cases, treatment with protease inhibitors was continued or restarted and some patients required additional factor VIII. A causal relationship between protease inhibitor therapy and these episodes has not been established.

Hepatic

Hepatic side effects have included chronic active hepatitis, hepatitis, hepatomegaly, hyperbilirubinemia, jaundice, portal hypertension, elevated ALT, elevated AST, and elevated gamma glutamyl transpeptidase. Sclerosing cholangitis, cholelithiasis, hepatosplenomegaly, and liver enzyme disorder have also been reported. Severe cutaneous reactions associated with elevated liver function tests, isolated increase in transaminase, and exacerbation of chronic liver disease with Grade 4 elevated liver function tests have been reported. There have been reports of worsening liver disease in patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism, and/or other underlying liver abnormalities.

Hypersensitivity

Hypersensitivity side effects have included allergic reaction. Drug fever, Stevens-Johnson syndrome, and bullous skin eruption and polyarthritis have also been reported.

Immunologic

Immunologic side effects have included abscess, angina tonsillaris, bacterial infection, candidiasis, cellulitis, cytomegalovirus retinitis, herpes simplex, herpes zoster, influenza, molluscum contagiosum, moniliasis, mycotic infection, staphylococcal infections, and tumor. Immune reconstitution syndrome has been reported with combination antiretroviral therapy, including saquinavir.

Nervous system

Nervous system side effects have included headache, confusion, convulsions, abnormal coordination, dizziness, dysgeusia, hypoesthesia, insomnia, intracranial hemorrhage leading to death, tremors, unconsciousness, paresthesia, peripheral neuropathy, somnolence, sleep disorder, syncope, and tinnitus. Dysarthria, dysesthesia, ataxia, extremity numbness, face numbness, facial pain, hyperesthesia, hyperreflexia, hyporeflexia, lightheadedness, myelopolyradiculoneuritis, paresis, poliomyelitis, prickly sensation, progressive multifocal leukoencephalopathy, seizures, spasms, weakness, and decreased hearing have also been reported.

Psychiatric

Psychiatric side effects have included anxiety, depression, libido disorder, psychotic disorder, and suicide attempt. Agitation, amnesia, anxiety attack, euphoria, excessive dreaming, hallucination, irritability, lethargy, overdose effect, psychic disorders, psychosis, reduced intellectual ability, somnolence, and speech disorder have also been reported.

Genitourinary

Genitourinary side effects have included enlarged prostate, epididymitis, impotence, menstrual disorder, menstrual irregularity, micturition disorder, nocturia, pelvic pain, penis disorder, renal calculus, renal colic, urinary tract bleeding, urinary tract infection, and vaginal discharge.

Ocular

Ocular side effects have included visual impairment. Chalazion, blepharitis, dry eye syndrome, eye irritation, visual disturbance, and xerophthalmia have also been reported.

Oncologic

Oncologic side effects have included acute myeloid leukemia and papillomatosis.

Renal

Renal side effects have included nephrolithiasis and acute renal insufficiency.

Endocrine

Endocrine side effects have included increased TSH and, rarely, hyperprolactinemia.

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