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Fortovase (Saquinavir) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

(SEE PRECAUTIONS)

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 EventsIncludes 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). of at Least Moderate Intensity, Occurring in ≥2% of Patients
NV15182
(48 weeks)
NV15355
(48 weeks)
Naive Patients
ADVERSE EVENTFORTOVASE + TOCAntiretroviral Treatment of Choice.
N=442
FORTOVASE+ 2 RTIsReverse Transcriptase Inhibitor.
N=90
Gastrointestinal
Diarrhea19.915.6
Nausea10.613.3
Abdominal Discomfort8.610.0
Dyspepsia8.47.8
Flatulence5.710.0
Vomiting2.94.4
Abdoiminal Pain2.34.4
Constipation3.3
Body as a Whole
Fatigue4.88.9
Appetite Decreased2.2
Chest Pain2.2
Central and Peripheral Nervous System
Headaches
5.05.6
Psychiatric Disorders
Depression2.7
Insomnia5.6
Anxiety2.2
Libido Disorder3.3
Special Senses Disorders
Taste Alteration4.4
Musculoskeletal Disorders
Pain3.3
Dermatological Disorders
Eczema
Rash
Verruca2.2

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/hyperglycemia4 (2.7)
  Lipodystrophy8 (5.4)
Gastrointestinal Disorders
  Nausea16 (10.8)
  Vomiting11 (7.4)
  Diarrhea12 (8.1)
  Abdominal Pain9 (6.1)
  Constipation3 (2.0)
General Disorders and Administration Site Conditions
  Fatigue9 (6.1)
  Fever5 (3.4)
Musculoskeletal Disorders
  Back Pain3 (2.0)
Respiratory Disorders
  Pneumonia8 (5.4)
  Bronchitis4 (2.7)
  Influenza4 (2.7)
  Sinusitis4 (2.7)
Dermatological Disorders
  Rash5 (3.4)
  Pruritus5 (3.4)
  Dry lips/skin3 (2.0)
  Eczema3 (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 AbnormalitiesACTG Grade 3 or above.
NV15182
(48 weeks)
NV15355
(48 weeks)
Naive Patients
FORTOVASE + TOCAntiretroviral Treatment of Choice.
N=442
FORTOVASE + 2 RTIsReverse Transcriptase Inhibitor.
N=90
ND Not done.
BIOCHEMISTRY Limit
Alkaline Phosphatase (high)>5 × ULN 1 0.50.0
Calcium (high)>12.5 mg/dL0.20.0
Creatine Kinase (high)>4 × ULN7.86.0
Gamma GT (high)>5 × ULN5.75.0
Glucose (low)<40 mg/dL6.43.5
Glucose (high)>250 mg/dL1.40.0
Phosphate (low)<1.5 mg/dL0.51.0
Potassium (high)>6.5 mEq/L2.73.5
Serum Amylase (high)>2 × ULN1.9ND
SGOT (AST) (high)>5 × ULN4.10.0
SGPT (ALT) (high)>5 × ULN5.71.0
Sodium (high)>157 mEq/L0.70.0
Sodium (low)<123 mEq/L0.01.0
Total Bilirubin (high)>2.5 × ULN1.60.0
Triglycerides (high)>750 mg/dL0.02.0
HEMATOLOGY
Hemoglobin (low)<7.0 gm/dL0.71.0
Absolute Neutrophil Count (low)<750 mm32.91.0
Platelets (low)<50,000 mm30.90.0

1 ULN = Upper limit of normal range.

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 (see PRECAUTIONS: Fat Redistribution)

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.

Drug label data at the top of this Page last updated: 2006-04-07

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