Fortovase Side Effects

Please note - some side effects for Fortovase 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 Fortovase - for the Consumer

Fortovase

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 Fortovase:

Anxiety; blurred vision; bronchitis; change in sexual ability; constipation; diarrhea; dry lips/skin; gas; headache; heartburn; loss of appetite; nausea; night sweats; sleeplessness; stomach discomfort; taste change; tiredness; vomiting; warts; weight gain.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); back pain; bloody stools; body fat changes; chest pain; confusion; coughing up blood; dark urine; difficulty urinating; dizziness; excessive thirst, hunger, or urination; fast heartbeat; fever; flu-like symptoms; fruity breath odor; itching; loss of coordination; mental or mood changes; muscle pain; numbness or tingling; pneumonia; seizures; shortness of breath; slow onset of drowsiness; stomach pain or tenderness; tenderness or bleeding of gums; thoughts of hurting yourself; unusual vaginal discharge or odor; unusual weakness; white patches in 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. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch .

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Fortovase Side Effects - for the Professional

Fortovase

The safety of Fortovase was studied in more than 500 patients who received the drug either alone or in combination with other antiretroviral agents. The majority of treatment-related adverse events were of mild intensity. The most frequently reported treatment-emergent adverse events among patients receiving Fortovase in combination with other antiretroviral agents were diarrhea, nausea, abdominal discomfort, and dyspepsia.

Clinical adverse events of at least moderate intensity, which occurred in ≥2% of patients in studies NV15182 (an open-label, single-arm safety study) and NV15355 (an open-label randomized study comparing Fortovase and INVIRASE) are summarized in Table 7. The median duration of treatment in studies NV15182 and NV15355 were 52 and 18 weeks, respectively. In NV15182, more than 300 patients were on treatment for approximately 1 year.

Fortovase did not appear to alter the pattern, frequency or severity of known major toxicities associated with the use of nucleoside analogues. Physicians should refer to the complete product information for other antiretroviral agents as appropriate for drug-associated adverse reactions to these other agents.

Rare occurrences of the following serious adverse experiences have been reported during clinical trials of Fortovase and/or INVIRASE and were considered at least possibly related to use of study drugs: confusion, ataxia and weakness; seizures; headache; acute myeloblastic leukemia; hemolytic anemia; thrombocytopenia; thrombocytopenia and intracranial hemorrhage leading to death; attempted suicide; Stevens-Johnson syndrome; bullous skin eruption and polyarthritis; severe cutaneous reaction associated with increased liver function tests; isolated elevation of transaminases; exacerbation of chronic liver disease with Grade 4 elevated liver function tests, jaundice, ascites, and right and left upper quadrant abdominal pain; pancreatitis leading to death; intestinal obstruction; portal hypertension; thrombophlebitis; peripheral vasoconstriction; drug fever; nephrolithiasis; and acute renal insufficiency.

Table 7 Percentage of Patients With Treatment-Emergent Adverse Events* of at Least Moderate Intensity, Occurring in ≥2% of Patients

	NV15182 (48 weeks)	NV15355 (48 weeks) Naive Patients
ADVERSE EVENT	Fortovase + TOC† N=442	Fortovase+ 2 RTIs‡ N=90
* Includes adverse events at least possibly related to study drug or of unknown intensity and/or relationship to treatment (corresponding to ACTG Grade 2, 3 and 4). † Antiretroviral Treatment of Choice. ‡ Reverse Transcriptase Inhibitor.
Gastrointestinal
Diarrhea	19.9	15.6
Nausea	10.6	13.3
Abdominal Discomfort	8.6	10.0
Dyspepsia	8.4	7.8
Flatulence	5.7	10.0
Vomiting	2.9	4.4
Abdoiminal Pain	2.3	4.4
Constipation	–	3.3
Body as a Whole
Fatigue	4.8	8.9
Appetite Decreased	–	2.2
Chest Pain	–	2.2
Central and Peripheral Nervous System
Headaches
	5.0	5.6
Psychiatric Disorders
Depression	2.7	–
Insomnia	–	5.6
Anxiety	–	2.2
Libido Disorder	–	3.3
Special Senses Disorders
Taste Alteration	–	4.4
Musculoskeletal Disorders
Pain	–	3.3
Dermatological Disorders
Eczema	–	–
Rash	–	–
Verruca	–	2.2

Concomitant Therapy with Ritonavir

Table 8 Grade 2, 3 and 4 Adverse Events (All Causality) Reported in ≥2% of Adult Patients in the MaxCmin 1 Study of Fortovase in Combination with Ritonavir 1000/100 mg bid

	Fortovase 1000 mg plus Ritonavir 100 mg bid (48 weeks) N=148 n(%=n/N)
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)

Includes events with unknown relationship to study drug.

Laboratory Abnormalities

In the MaxCmin 1 study, Grade 3 and 4 thrombocytopenia (2.0% of patients) and anemia (2.0%) were observed with Fortovase in combination with ritonavir. At 48 weeks, other lab abnormalities included increased ALT, increased AST, increased GGT, hyperglycemia, hypertriglyceridemia, increased TSH, neutropenia, raised amylase, and increased LDH.

Table 9 summarizes the percentage of patients with marked laboratory abnormalities in study NV15182 and NV15355 (median duration of treatment was 52 and 18 weeks, respectively). In study NV15182, by 48 weeks <1% of patients discontinued treatment due to laboratory abnormalities.

In the safety study (NV15182), 27% to 33% of subjects experienced ≥1 grade shifts in ALT and AST during the 48-week study period. In 46% of such events, there was a single abnormal transaminase level with no evidence of persistently elevated enzyme values during the course of study. Only 3% to 4% of patients had ≥3 grade shifts in transaminase levels and less than 0.5% of patients had to discontinue the study for increased liver function test values.

Table 9 Percentage of Patients with Marked Laboratory Abnormalities*

		NV15182 (48 weeks)	NV15355 (48 weeks) Naive Patients
		Fortovase + TOC† N=442	Fortovase + 2 RTIs‡ N=90
ND Not done.
* ACTG Grade 3 or above. † Antiretroviral Treatment of Choice. ‡ Reverse Transcriptase Inhibitor. § ULN = Upper limit of normal range.
BIOCHEMISTRY	Limit
Alkaline Phosphatase (high)	>5 × ULN§	0.5	0.0
Calcium (high)	>12.5 mg/dL	0.2	0.0
Creatine Kinase (high)	>4 × ULN§	7.8	6.0
Gamma GT (high)	>5 × ULN§	5.7	5.0
Glucose (low)	<40 mg/dL	6.4	3.5
Glucose (high)	>250 mg/dL	1.4	0.0
Phosphate (low)	<1.5 mg/dL	0.5	1.0
Potassium (high)	>6.5 mEq/L	2.7	3.5
Serum Amylase (high)	>2 × ULN§	1.9	ND
SGOT (AST) (high)	>5 × ULN§	4.1	0.0
SGPT (ALT) (high)	>5 × ULN§	5.7	1.0
Sodium (high)	>157 mEq/L	0.7	0.0
Sodium (low)	<123 mEq/L	0.0	1.0
Total Bilirubin (high)	>2.5 × ULN§	1.6	0.0
Triglycerides (high)	>750 mg/dL	0.0	2.0
HEMATOLOGY
Hemoglobin (low)	<7.0 gm/dL	0.7	1.0
Absolute Neutrophil Count (low)	<750 mm3	2.9	1.0
Platelets (low)	<50,000 mm3	0.9	0.0

Additional marked lab abnormalities have been observed with INVIRASE. These include: calcium (low), phosphate (low), potassium (low), sodium (low).

Monotherapy and Combination Studies

Other clinical adverse experiences of any intensity, at least remotely related to Fortovase and INVIRASE, including those in <2% of patients, are listed below by body system.

Autonomic Nervous System

Mouth dry, night sweats, sweating increased

Body as a Whole

Allergic reaction, anorexia, appetite decreased, appetite disturbances, asthenia, chest pain, edema, fever, intoxication, malaise, olfactory disorder, pain body, pain pelvic, retrosternal pain, shivering, trauma, wasting syndrome, weakness generalized, weight decrease, redistribution/accumulation of body fat

Cardiovascular/Cerebrovascular

Cyanosis, heart murmur, heart rate disorder, heart valve disorder, hypertension, hypotension, stroke, syncope, vein distended

Central and Peripheral Nervous System

Ataxia, cerebral hemorrhage, confusion, convulsions, dizziness, dysarthria, dysesthesia, hyperesthesia, hyperreflexia, hyporeflexia, light-headed feeling, myelopolyradiculoneuritis, neuropathy, numbness extremities, numbness face, paresis, paresthesis, peripheral neuropathy, poliomyelitis, prickly sensation, progressive multifocal leukoencephalopathy, spasms, tremor, unconsciousness

Dermatological

Acne, alopecia, chalazion, dermatitis, dermatitis seborrheic, erythema, folliculitis, furunculosis, hair changes, hot flushes, nail disorder, papillomatosis, papular rash, photosensitivity reaction, pigment changes skin, parasites external, pruritus, psoriasis, rash maculopapular, rash pruritic, red face, skin disorder, skin nodule, skin syndrome, skin ulceration, urticaria, verruca, xeroderma

Endocrine/Metabolic

Dehydration, diabetes mellitus, hyperglycemia, hypoglycemia, hypothyroidism, thirst, triglyceride increase, weight increase

Gastrointestinal

Abdominal distention, bowel movements frequent, buccal mucosa ulceration, canker sores oral, cheilitis, colic abdominal, dysphagia, esophageal ulceration, esophagitis, eructation, fecal incontinence, feces bloodstained, feces discolored, gastralgia, gastritis, gastroesophageal reflux, gastrointestinal inflammation, gingivitis, glossitis, hemorrhage rectum, hemorrhoids, infectious diarrhea, melena, painful defecation, parotid disorder, pruritus ani, pyrosis, salivary glands disorder, stomach upset, stomatitis, taste unpleasant, toothache, tooth disorder, ulcer gastrointestinal

Hematologic

Anemia, neutropenia, pancytopenia, splenomegaly

Liver and Biliary

Cholangitis sclerosing, cholelithiasis, hepatitis, hepatomegaly, hepatosplenomegaly, jaundice, liver enzyme disorder, pancreatitis

Musculoskeletal

Arthralgia, arthritis, back pain, cramps leg, cramps muscle, lumbago, musculoskeletal disorders, myalgia, myopathy, pain facial, pain jaw, pain leg, pain musculoskeletal, stiffness, tissue changes

Neoplasm

Kaposi's sarcoma, tumor

Platelet, Bleeding, Clotting

Bleeding dermal, hemorrhage, microhemorrhages, thrombocytopenia

Psychiatric

Agitation, amnesia, anxiety attack, behavior disturbances, dreaming excessive, euphoria, hallucination, intellectual ability reduced, irritability, lethargy, overdose effect, psychic disorder, psychosis, somnolence, speech disorder

Reproductive System

Epididymitis, erectile impotence, impotence, menstrual disorder, menstrual irregularity, penis disorder, prostate enlarged, vaginal discharge

Resistance Mechanism

Abscess, angina tonsillaris, candidiasis, cellulitis, herpes simplex, herpes zoster, infection bacterial, infection mycotic, infection staphylococcal, infestation parasitic, influenza, lymphadenopathy, molluscum contagiosum, moniliasis

Respiratory

Asthma bronchial, bronchitis, cough, dyspnea, epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary disease, respiratory disorder, rhinitis, rhinitis allergic atopic, sinusitis, upper respiratory tract infection

Special Senses

Blepharitis, conjunctivitis, cytomegalovirus retinitis, dry eye syndrome, earache, ear pressure, eye irritation, hearing decreased, otitis, taste unpleasant, tinnitus, visual disturbance, xerophthalmia

Urinary System

Micturition disorder, nocturia, renal calculus, renal colic, urinary tract bleeding, urinary tract infection

Postmarketing Experience with INVIRASE and Fortovase

Additional adverse events that have been observed during the postmarketing period are similar to those seen in clinical trials with INVIRASE and Fortovase and administration of INVIRASE and Fortovase in combination with ritonavir.

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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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