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 at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

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; loss of appetite; mouth sores; nausea; night sweats; sleeplessness; stomach discomfort; taste changes; tenderness or bleeding of the gums; tiredness; vomiting; warts; weight gain.

Severe allergic reactions (rash; hives; 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; fast heartbeat; fever; flu-like symptoms; itching; loss of coordination; numbness or tingling; pain in muscles or joints; reddened, blistered, or swollen skin; seizures; shortness of breath; stomach pain or tenderness; unusual bruising or bleeding; unusual vaginal discharge or odor; unusual weakness; white patches in mouth; yellowing of the skin or eyes.

Invirase Side Effects - for the Professional

Invirase

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).

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.

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

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.

Side Effects by Body System

General

Gastrointestinal side effects have been reported the most frequently with the saquinavir soft gel capsule (SGC) formulation. The saquinavir hard gelatin capsule (HGC) formulation may have better gastrointestinal tolerance. The most common adverse effects associated with saquinavir in combination with other antiretroviral agents have included diarrhea, nausea, abdominal discomfort, and dyspepsia.

Gastrointestinal

Gastrointestinal (GI) side effects have included diarrhea (19.9%), nausea (10.6%), abdominal discomfort (8.6%), dyspepsia (8.4%), flatulence (5.7%), vomiting (2.9%), and abdominal pain (2.3%) during a noncomparative tolerability trial with saquinavir SGC and 2 or more other antiretroviral agents. Other GI side effects have included anorexia, decreased appetite, buccal mucosal ulceration, cheilitis, colic, constipation, dysphagia, esophageal ulceration, esophagitis, eructation, discolored and bloodstained feces, gastralgia, gastroesophageal reflux, gastritis, GI inflammation, gingivitis, GI ulcer, glossitis, hemorrhoids, infectious diarrhea, intestinal obstruction, melena, painful defecation, pancreatitis (including fatalities), parotid disorder, pruritus ani, pyrosis, rectal hemorrhage, salivary gland disorder, stomach upset, stomatitis, taste disturbances, toothache, and tooth disorder.

Cardiovascular

Cardiovascular side effects have rarely included chest pain, cyanosis, edema, heart murmur, heart rate disorder, heart valve disorder, hypertension, hypotension, fatal intracranial hemorrhage, peripheral vasoconstriction, stroke, syncope, thrombophlebitis, and vein distension.

Dermatologic

Dermatologic side effects have included skin rash and pruritus in 2% to 3% of patients. Less common side effects have included acne, alopecia, dermatitis, dry skin and lips, eczema, erythema, exanthema, folliculitis, furunculosis, hair changes, hot flushes, increased sweating, maculopapular rash, nail disorders, night sweats, papillomatosis, photosensitivity reaction, psoriasis, seborrheic dermatitis, skin disorder, skin nodule, skin pigment changes, skin ulceration, urticaria, verruca, and xeroderma.

Endocrine

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

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.

Hematologic

Hematologic side effects have included anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, dermal bleeding, microhemorrhages, and thrombocytopenia leading to death. 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 ascites, sclerosing cholangitis, cholelithiasis, hepatitis, hepatomegaly, hepatosplenomegaly, jaundice, liver enzyme disorder, and elevated ALT, AST, amylase, alkaline phosphatase, gamma glutamyl transpeptidase, and LDH. 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. Although a causal relationship has not been established, there have been reports of exacerbation of chronic liver dysfunction, including portal hypertension, in patients with underlying hepatitis B or C, cirrhosis, or other underlying liver abnormalities.

Hypersensitivity

Hypersensitivity side effects have included drug fever, Stevens-Johnson syndrome, and bullous skin eruption and polyarthritis.

Immunologic

Immunologic side effects related to the resistance mechanism have included abscess, angina tonsillaris, bacterial infection, candidiasis, cellulitis, cytomegalovirus retinitis, herpes simplex, herpes zoster, influenza, lymphadenopathy, molluscum contagiosum, moniliasis, mycotic infection, staphylococcal infections, and tumor.

Metabolic

Metabolic side effects have included dehydration, appetite disturbance, hypertriglyceridemia, hyperglycemia, diabetes, hypoglycemia, hypercalcemia, hypocalcemia, hyperphosphatemia, hypophosphatemia, hyperkalemia, hypokalemia, hypernatremia, hyponatremia, hyperbilirubinemia, hyperlipidemia, weight decrease, and weight increase.

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.

Musculoskeletal

Musculoskeletal side effects have included arthralgia, arthritis, back pain, elevated creatine phosphokinase, leg cramps, muscle cramps, musculoskeletal pain, musculoskeletal disorders, myalgia, stiffness, tissue changes, and trauma.

Nervous system

Nervous system side effects have included headache (5%), and less commonly, ataxia, confusion, convulsions, dizziness, dysarthria, dysesthesia, extremity numbness, face numbness, facial pain, frequent bowel movements, hyperesthesia, hyperreflexia, hyporeflexia, insomnia, lightheadedness, dry mouth, myelopolyradiculoneuritis, paresis, paresthesia, peripheral neuropathy, poliomyelitis, prickly sensation, progressive multifocal leukoencephalopathy, seizures, somnolence, spasms, tremors, unconsciousness, weakness, decreased hearing, and tinnitus.

Ocular

Ocular side effects have included blepharitis, dry eye syndrome, eye irritation, visual disturbance, and xerophthalmia.

Oncologic

Oncologic side effects have rarely included acute myeloblastic leukemia.

Psychiatric

Psychiatric side effects have included agitation, amnesia, anxiety, anxiety attack, depression, euphoria, excessive dreaming, hallucination, irritability, lethargy, libido disorder, psychic disorders, psychosis, reduced intellectual ability, somnolence, speech disorder, and suicide attempt.

Renal

Renal side effects have included nephrolithiasis and acute renal insufficiency.

Respiratory

Respiratory side effects have included bronchitis, cough, dyspnea, epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary disease, respiratory disorder, rhinitis, sinusitis, and upper respiratory tract infection.

Other

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. The mechanism and long-term consequences of these events are currently unknown and a causal relationship has not been established.

Other

Other side effects have included fatigue, fever, intoxication, asthenia, mucosa damage, external parasites, retrosternal pain, shivering, wasting syndrome, generalized weakness, earache, and otitis.

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