Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/275
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
NORVIR (Capsule)
|
| dailymed-instance:dosage |
NORVIR is administered orally.
It is recommended that NORVIR be taken with meals if possible. Patients
may improve the taste of NORVIR oral solution by mixing with chocolate
milk, Ensure, or Advera within one
hour of dosing. The effects of antacids on the absorption of ritonavir
have not been studied.<br/>Adults:<br/>Recommended Dosage: The recommended dosage of ritonavir is 600 mg twice
daily by mouth. Use of a dose titration schedule may help to reduce
treatment-emergent adverse events while maintaining appropriate ritonavir
plasma levels. Ritonavir should be started at no less than 300 mg
twice daily and increased at 2 to 3 day intervals by 100 mg twice
daily.<br/>Pediatric Patients: Ritonavir should
be used in combination with other antiretroviral agents (see General Dosing Guidelines ). The recommended
dosage of ritonavir in children>1 month is 350 to 400 mg/mtwice daily by mouth and should not exceed 600 mg twice daily.
Ritonavir should be started at 250 mg/mand increased
at 2 to 3 day intervals by 50 mg/mtwice daily. If patients
do not tolerate 400 mg/mtwice daily due to adverse events,
the highest tolerated dose may be used for maintenance therapy in
combination with other antiretroviral agents, however, alternative
therapy should be considered. When possible, dose should be administered
using a calibrated dosing syringe.<br/>General Dosing Guidelines: Patients should
be aware that frequently observed adverse events, such as mild to
moderate gastrointestinal disturbances and paraesthesias, may diminish
as therapy is continued. In addition, patients initiating combination
regimens with NORVIR and reverse transcriptase inhibitors may improve
gastrointestinal tolerance by initiating NORVIR alone and subsequently
adding reverse transcriptase inhibitors before completing two weeks
of NORVIR monotherapy.
|
| dailymed-instance:descripti... |
NORVIR (ritonavir) is an
inhibitor of HIV protease with activity against the Human Immunodeficiency
Virus (HIV). Ritonavir
is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-
[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-
tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)].
Its molecular formula is CHNOS, and its molecular weight is 720.95.
Ritonavir has the following structural formula: Ritonavir is a white-to-light-tan
powder. Ritonavir has a bitter metallic taste. It is freely soluble
in methanol and ethanol, soluble in isopropanol and practically insoluble
in water. NORVIR soft
gelatin capsules are available for oral administration in a strength
of 100 mg ritonavir with the following inactive ingredients:
Butylated hydroxytoluene, ethanol, gelatin, iron oxide, oleic acid,
polyoxyl 35 castor oil, and titanium dioxide. NORVIR oral solution is available for oral administration as 80 mg/mL
of ritonavir in a peppermint and caramel flavored vehicle. Each 8-ounce
bottle contains 19.2 grams of ritonavir. NORVIR oral solution also
contains ethanol, water, polyoxyl 35 castor oil, propylene glycol,
anhydrous citric acid to adjust pH, saccharin sodium, peppermint oil,
creamy caramel flavoring, and FD&C Yellow No. 6.
|
| dailymed-instance:clinicalP... |
Microbiology:<br/>Mechanism of Action: Ritonavir
is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases.
Inhibition of HIV protease renders the enzyme incapable of processing
the gag-pol polyprotein precursor
which leads to production of non-infectious immature HIV particles.<br/>Antiviral Activity In Vitro: The activity
of ritonavir was assessed in vitro in acutely infected lymphoblastoid cell lines and in peripheral
blood lymphocytes. The concentration of drug that inhibits 50% (EC) of viral replication ranged from 3.8 to 153 nM depending
upon the HIV-1 isolate and the cells employed. The average ECfor low passage clinical isolates was 22 nM (n = 13).
In MTcells, ritonavir demonstrated additive effects
against HIV-1 in combination with either zidovudine (ZDV) or didanosine
(ddI). Studies which measured cytotoxicity of ritonavir on several
cell lines showed that>20��M was required to inhibit cellular
growth by 50% resulting in an in vitro therapeutic index of at least 1000.<br/>Resistance: HIV-1 isolates
with reduced susceptibility to ritonavir have been selected in vitro. Genotypic analysis of these
isolates showed mutations in the HIV protease gene at amino acid positions
84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46 (Met to
Ile). Phenotypic (n = 18) and genotypic (n = 44) changes in HIV isolates
from selected patients treated with ritonavir were monitored in phase
I/II trials over a period of 3 to 32 weeks. Mutations associated
with the HIV viral protease in isolates obtained from 41 patients
appeared to occur in a stepwise and ordered fashion; in sequence,
these mutations were position 82 (Val toAla/Phe), 54 (Ile to Val),
71 (Ala to Val/Thr), and 36 (Ile to Leu), followed by combinations
of mutations at an additional 5 specific amino acid positions. Of
18 patients for whom both phenotypic and genotypic analysis were performed
on free virus isolated from plasma, 12 showed reduced susceptibility
to ritonavir in vitro. All
18 patients possessed one or more mutations in the viral protease
gene. The 82 mutation appeared to be necessary but not sufficient
to confer phenotypic resistance. Phenotypic resistance was defined
as a���5-fold decrease in viral sensitivity in vitro from baseline. The clinical
relevance of phenotypic and genotypic changes associated with ritonavir
therapy has not been established.<br/>Cross-Resistance to Other Antiretrovirals: Among protease
inhibitors variable cross-resistance has been recognized. Serial
HIV isolates obtained from six patients during ritonavir therapy
showed a decrease in ritonavir susceptibility in vitro but did not demonstrate a concordant
decrease in susceptibility to saquinavir in vitro when compared to matched baseline isolates.
However, isolates from two of these patients demonstrated decreased
susceptibility to indinavir in vitro (8-fold). Isolates from 5 patients were also tested for cross-resistance
to amprenavir and nelfinavir; isolates from 2 patients had a decreasein susceptibility to nelfinavir (12- to 14-fold), and none to amprenavir.
Cross-resistance between ritonavir and reverse transcriptase inhibitors
is unlikely because of the different enzyme targets involved. One
ZDV-resistant HIV isolate tested in vitro
retained full susceptibility to ritonavir.<br/>Pharmacokinetics: The pharmacokinetics
of ritonavir have been studied in healthy volunteers and HIV-infected
patients (CD���50 cells/��L). See Table
1 for ritonavir pharmacokinetic characteristics.<br/>Absorption: The absolute
bioavailability of ritonavir has not been determined. After a 600
mg dose of oral solution, peak concentrations of ritonavir were achieved
approximately 2 hours and 4 hours after dosing under fasting
and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate)
conditions, respectively.<br/>Effect of Food on Oral Absorption: When the
oral solution was given under non-fasting conditions, peak ritonavir
concentrations decreased 23% and the extent of absorption decreased
7% relative to fasting conditions. Dilution of the oral solution,
within one hour of administration, with 240 mL of chocolate milk,
Advera or Ensure did not significantly
affect the extent and rate of ritonavir absorption. After a single
600 mg dose under non-fasting conditions, in two separate studies,
the soft gelatin capsule (n = 57) and oral solution (n = 18) formulations
yielded mean��SD areas under the plasma concentration-time curve
(AUCs) of 121.7��53.8 and 129.0��39.3��g���h/mL, respectively. Relative to
fasting conditions, the extent of absorption of ritonavir from the
soft gelatin capsule formulation was 13% higher when administered
with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate).<br/>Metabolism: Nearly all
of the plasma radioactivity after a single oral 600 mg dose ofC-ritonavir oral solution (n = 5) was attributed to unchanged
ritonavir. Five ritonavir metabolites have been identified in human
urine and feces. The isopropylthiazole oxidation metabolite (M-2)
is the major metabolite and has antiviral activity similar to that
of parent drug; however, the concentrations of this metabolite in
plasma are low. In vitro studies
utilizing human liver microsomes have demonstrated that cytochrome
P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism,
although CYP2D6 also contributes to the formation of M-2.<br/>Elimination: In a study
of five subjects receiving a 600 mg dose ofC-ritonavir
oral solution, 11.3��2.8% of the dose was excreted
into the urine, with 3.5��1.8% of the dose excreted as unchanged
parent drug. In that study, 86.4��2.9% of the dose was excreted
in the feces with 33.8��10.8% of the dose excreted as unchanged
parent drug. Upon multiple dosing, ritonavir accumulation is less
than predicted from a single dose possibly due to a time and dose-related
increase in clearance.<br/>Effects on Electrocardiogram: QTcF interval was evaluated in a randomized, placebo
and active (moxifloxacin 400 mg once-daily) controlled crossover study
in 45 healthy adults, with 10 measurements over 12 hours on Day 3.
The maximum mean (95% upper confidence bound) time-matched difference
in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds
(msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice dailyresulted in Day 3 ritonavir exposure that was approximately 1.5 fold
higher than observed with ritonavir 600 mg twice-daily dose at steady
state. PR interval prolongation was also
noted in subjects receiving ritonavir in the same study on Day 3.
The maximum mean (95% confidence interval) difference from placebo
in the PR interval after baseline correction was 22 (25) msec for
400 mg twice-daily ritonavir. See PRECAUTIONS���PR Interval Prolongation.<br/>Special Populations:
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
NORVIR is contraindicated
in patients with known hypersensitivity to ritonavir or any of its
ingredients. Co-administration
of NORVIR is contraindicated with the drugs listed in Table 4 (also
see PRECAUTIONS - Table 5. Drugs that Should
Not be Co-administered with NORVIR) because competition
for primarily CYP3A by ritonavir could result in inhibition of the
metabolism of these drugs and create the potential for serious and/or
life-threatening reactions such as cardiac arrhythmias, prolonged
or increased sedation, and respiratory depression. Voriconazole is
an exception in that co-administration of Norvir and Voriconazole
results in a significant decrease in plasma concentrations of Voriconazole.
|
| dailymed-instance:supply |
NORVIR (ritonavir capsules) soft gelatin are white
capsules imprinted with the corporate Abbott���A���logo, 100 and the Abbo-Code DS, available
in the following package size: Bottles of 120 capsules each (NDC 0074-6633-22).Bottles of 30 capsules each (NDC 0074-6633-30).<br/>Recommended Storage: Store soft gelatin
capsules in the refrigerator between 36-46��F (2-8��C) until
dispensed. Refrigeration of NORVIR soft gelatin capsules by the patient
is recommended, but not required if used within 30 days and stored
below 77��F (25��C). Protect from light. Avoid exposure
to excessive heat. NORVIR (ritonavir oral solution) is an orange-colored
liquid, supplied in amber-colored, multi-dose bottles containing 600
mg ritonavir per 7.5 mL marked dosage cup (80 mg/mL) in the following
size: 240 mL bottles
(NDC 0074-1940-63).<br/>Recommended Storage: Store NORVIR oral
solution at room temperature 68��F to 77��F (20��C to
25��C). Do not refrigerate. Shake well before each use. Use
by product expiration date. Product should be stored and dispensed in the original container. Avoid exposure to excessive
heat. Keep cap tightly closed.
|
| dailymed-instance:genericDr... | |
| dailymed-instance:boxedWarn... |
WARNING CO-ADMINISTRATION OF NORVIR WITH CERTAIN NONSEDATING
ANTIHISTAMINES, SEDATIVE HYPNOTICS, ANTIARRHYTHMICS, OR ERGOT ALKALOID
PREPARATIONS MAY RESULT IN POTENTIALLY SERIOUS AND/OR LIFE-THREATENING
ADVERSE EVENTS DUE TO POSSIBLE EFFECTS OF NORVIR ON THE HEPATIC METABOLISM
OF CERTAIN DRUGS. SEE CONTRAINDICATIONS AND PRECAUTIONS SECTIONS.
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:overdosag... |
Acute Overdosage:<br/>Human Overdose Experience: Human experience
of acute overdose with NORVIR is limited. One patient in clinical
trials took NORVIR 1500 mg/day for two days. The patient reported
paresthesias which resolved after the dose was decreased. A post-marketing
case of renal failure with eosinophilia has been reported with ritonavir
overdose. The approximate lethal dose was found to be greater than 20 times
the related human dose in rats and 10 times the related human dose
in mice.<br/>Management of Overdosage: NORVIR oral solution
contains 43% alcohol by volume. Accidental ingestion of the product
by a young child could result in significant alcohol-related toxicity
and could approach the potential lethal dose of alcohol. Treatment of overdose with
NORVIR consists of general supportive measures including monitoring
of vital signs and observation of the clinical status of the patient.
There is no specific antidote for overdose with NORVIR. If indicated,
elimination of unabsorbed drug should be achieved by emesis or gastric
lavage; usual precautions should be observed to maintain the airway.
Administration of activated charcoal may also be used to aid in removal
of unabsorbed drug. Since ritonavir is extensively metabolized by
the liver and is highly protein bound, dialysis is unlikely to be
beneficial in significant removal of the drug. A Certified Poison
Control Center should be consulted for up-to-date information on the
management of overdose with NORVIR.
|
| dailymed-instance:genericMe... |
ritonavir
|
| dailymed-instance:fullName |
NORVIR (Capsule)
|
| dailymed-instance:adverseRe... |
Adults: The safety of NORVIR alone
and in combination with nucleoside reverse transcriptase inhibitors
was studied in 1270 adult patients. Table 7 lists treatment-emergent
adverse events (at least possibly related and of at least moderate
intensity) that occurred in 2% or greater of adult patients receiving
NORVIR alone or in combination with nucleoside reverse transcriptase
inhibitors in Study 245 or Study 247 and in combination with saquinavir
in study 462. In that study, 141 protease inhibitor-naive, HIV-infected
patients with mean baseline CDof 300 cells/��L were
randomized to one of four regimens of NORVIR + saquinavir, including
NORVIR 400 mg twice-daily + saquinavir 400 mg twice-daily. Overall
the most frequently reported clinical adverse events, other than asthenia,
among adult patients receiving NORVIR were gastrointestinal and neurological
disturbances including nausea, diarrhea, vomiting, anorexia, abdominal
pain, taste perversion, and circumoral and peripheral paresthesias.
Similar adverse event profiles were reported in adult patients receiving
ritonavir in other trials. Adverse events occurring in less than
2% of adult patients receiving NORVIR in all phase II/phase III
studies and considered at least possibly related or of unknown relationship
to treatment and of at least moderate intensity are listed below by
body system.<br/>Body as a Whole: Abdomen enlarged,
accidental injury, allergic reaction, back pain, cachexia, chest pain,
chills, facial edema, facial pain, flu syndrome, hormone level altered,
hypothermia, kidney pain, neck pain, neck rigidity, pelvic pain, photosensitivity
reaction, and substernal chest pain.<br/>Cardiovascular System: Cardiovascular disorder,
cerebral ischemia, cerebral venous thrombosis, hypertension, hypotension,
migraine, myocardial infarct, palpitation, peripheral vascular disorder,
phlebitis, postural hypotension, tachycardia and vasospasm.<br/>Digestive System: Abnormal stools,
bloody diarrhea, cheilitis, cholestatic jaundice, colitis, dry mouth,
dysphagia, eructation, esophageal ulcer, esophagitis, gastritis, gastroenteritis,
gastrointestinal disorder, gastrointestinal hemorrhage, gingivitis,
hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, ileus,
liver damage, melena, mouth ulcer, pancreatitis, pseudomembranous
colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis,
tenesmus, thirst, tongue edema, and ulcerative colitis.<br/>Endocrine System: Adrenal cortex insufficiency
and diabetes mellitus.<br/>Hemic and Lymphatic System: Acute myeloblastic
leukemia, anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis,
myeloproliferative disorder, and thrombocytopenia.<br/>Metabolic and Nutritional Disorders: Albuminuria, alcohol
intolerance, avitaminosis, BUN increased, dehydration, edema, enzymatic
abnormality, glycosuria, gout, hypercholesteremia, peripheral edema,
and xanthomatosis.<br/>Musculoskeletal System: Arthritis, arthrosis,
bone disorder, bone pain, extraocular palsy, joint disorder, leg cramps,
muscle cramps, muscle weakness, myositis, and twitching.<br/>Nervous System: Abnormal dreams,
abnormal gait, agitation, amnesia, aphasia, ataxia, coma, convulsion,
dementia, depersonalization, diplopia, emotional lability, euphoria,
grand mal convulsion, hallucinations, hyperesthesia, hyperkinesia,
hypesthesia, incoordination, libido decreased, manic reaction, nervousness,
neuralgia, neuropathy, paralysis, peripheral neuropathic pain, peripheral
neuropathy, peripheral sensory neuropathy, personality disorder, sleep
disorder, speech disorder, stupor, subdural hematoma, tremor, urinary
retention, vertigo, and vestibular disorder.<br/>Respiratory System: Asthma, bronchitis,
dyspnea, epistaxis, hiccup, hypoventilation, increased cough, interstitial
pneumonia, larynx edema, lung disorder, rhinitis, and sinusitis.<br/>Skin and Appendages: Acne, contact dermatitis,
dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis,
fungal dermatitis, furunculosis, maculopapular rash, molluscum contagiosum,
onychomycosis, pruritus, psoriasis, pustular rash, seborrhea, skin
discoloration, skin disorder, skin hypertrophy, skin melanoma, urticaria,
and vesiculobullous rash.<br/>Special Senses: Abnormal electro-oculogram,
abnormal electroretinogram, abnormal vision, amblyopia/blurred vision,
blepharitis, conjunctivitis, ear pain, eye disorder, eye pain, hearing
impairment, increased cerumen, iritis, parosmia, photophobia, taste
loss, tinnitus, uveitis, visual field defect, and vitreous disorder.<br/>Urogenital System: Acute kidney failure,
breast pain, cystitis, dysuria, hematuria, impotence, kidney calculus,
kidney failure, kidney function abnormal, kidney pain, menorrhagia,
penis disorder, polyuria, urethritis, urinary frequency, urinary tract
infection, and vaginitis.<br/>Post-Marketing Experience: The following adverse
events have been reported during post-marketing use of NORVIR. Because
these reactions are reported voluntarily from a population of unknown
size, it is not possible to reliably estimate their frequency or establish
a causal relationship to NORVIR exposure.<br/>Laboratory Abnormalities: Table 8 shows the
percentage of adult patients who developed marked laboratory abnormalities.<br/>Pediatrics:<br/>Treatment-Emergent Adverse Events: NORVIR has been studied in 265 pediatric patients>1 month to 21 years of age. The adverse event profile observed
during pediatric clinical trials was similar to that for adult patients. Vomiting, diarrhea, and skin rash/allergy were the only
drug-related clinical adverse events of moderate to severe intensity
observed in���2% of pediatric patients enrolled in NORVIR clinical
trials.<br/>Laboratory Abnormalities: The following Grade 3-4 laboratory abnormalities
occurred in>3% of pediatric patients who received treatment with
NORVIR either alone or in combination with reverse transcriptase inhibitors:
neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia
(4%), and elevated AST (3%).
|
| dailymed-instance:warning |
ALERT: Find out about medicines that should NOT
be taken with NORVIR. This statement is included on the
product's bottle label.<br/>Drug Interactions: Ritonavir is an inhibitor of cytochrome P450 3A
(CYP3A) both in vitro and in vivo. Ritonavir also inhibits CYP2D6 in vitro, but to a lesser extent than
CYP3A. Co-administration of ritonavir and drugs primarily metabolized
by CYP3A or CYP2D6 may result in increased plasma concentrations of
other drugs that could increase or prolong its therapeutic and adverse
effects (see Pharmacokinetics - Drug-Drug Interactions, CONTRAINDICATIONS - Table 4. Drugs that are Contraindicated
with NORVIR, PRECAUTIONS - Table
5. Drugs that Should Not be Co-administered with NORVIR, Table 6. Established and Other Potentially Significant
Drug Interactions). The magnitude of the interactions and therapeutic consequences between
ritonavir and some of the drugs listed in Table 6. Established and Other Potentially Significant Drug Interactions cannot be predicted with any certainty. When co-administering ritonavir
with any agent listed in this table, special attention is warranted.
Refer to PRECAUTIONS - Drug Interactions for additional information. Cardiac and neurologic events have been reported with ritonavir when
co-administered with disopyramide, mexiletine, nefazodone, fluoxetine
and beta blockers. The possibility of drug interaction cannot be
excluded. Particular
caution should be used when prescribing PDE5 inhibitors for erectile
dysfunction (eg, sildenafil, tadalafil, or vardenafil) for patients
receiving protease inhibitors, including NORVIR. Co-administration
of NORVIR with a PDE5 inhibitor is expected to substantially increase
PDE5 inhibitor concentrations and may result in an increase in sildenafil-associated
adverse events, including hypotension, syncope, visual changes, and
prolonged erection (see PRECAUTIONS - Table
6. Established and Other Potentially Significant Drug Interactions and the complete prescribing information for sildenafil, tadalafil
and vardenafil). Concomitant use of NORVIR with lovastatin or simvastatin is not recommended.
Caution should be exercised if HIV protease inhibitors, including
NORVIR, are used concurrently with other HMG-CoA reductase inhibitors
that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin
or cerivastatin). The risk of myopathy including rhabdomyolysis may
be increased when HIV protease inhibitors, including NORVIR, are used
in combination with thesedrugs. Concomitant use of NORVIR, and St. John's wort (hypericum perforatum)
or products containing St. John's wort is not recommended.
Co-administration of protease inhibitors, including NORVIR, with
St. John's wort is expected to substantially decrease protease
inhibitor concentrations and may result in sub-optimal levels of NORVIR
and lead to loss of virologic response and possible resistance to
NORVIR or to the class of protease inhibitors. A drug interaction study in healthy subjects has shown that ritonavir
significantly increases plasma fluticasone propionate exposures, resulting
in significantly decreased serum cortisol concentrations. Systemic
corticosteroid effects, including Cushing's syndrome and adrenal
suppression have been reported during postmarketing use in patients
receiving ritonavir and inhaled or intranasally administered fluticasone
propionate. Therefore, co-administration of fluticasone propionate
and NORVIR is not recommended unless the potential benefit to the
patient outweighs the risk of systemic corticosteroid side effects
(see PRECAUTIONS - Drug Interactions). Tipranavir co-administered with 200 mg
of ritonavir has been associated with reports of clinical hepatitis
and hepatic decompensation including some fatalities. Extra vigilance
is warranted in patients with chronic hepatitis B or hepatitis C co-infection,
as these patients have an increased risk of hepatotoxicity.<br/>Allergic Reactions: Allergic reactions
including urticaria, mild skin eruptions, bronchospasm, and angioedema
have been reported. Rare cases of anaphylaxis and Stevens-Johnson
syndrome have also been reported.<br/>Hepatic Reactions: Hepatic transaminase
elevations exceeding 5 times the upper limit of normal, clinical hepatitis,
and jaundice have occurred in patients receiving NORVIR alone or in
combination with other antiretroviral drugs (see Table 8). There
may be an increased risk for transaminase elevations in patients with
underlying hepatitis B or C. Therefore, caution should be exercised
when administering NORVIR to patients with pre-existing liver diseases,
liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring
should be considered in these patients, especially during the first
three months of NORVIR treatment. There have been postmarketing reports of hepatic dysfunction, including
some fatalities. These have generally occurred in patients taking
multiple concomitant medications and/or with advanced AIDS.<br/>Pancreatitis: Pancreatitis has
been observed in patients receiving NORVIR therapy, including those
who developed hypertriglyceridemia. In some cases fatalities have
been observed. Patients with advanced HIV disease may be at increased
risk of elevated triglycerides and pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting,
abdominal pain) or abnormalities in laboratory values (such as increased
serum lipase or amylase values) suggestive of pancreatitis should
occur. Patients who exhibit these signs or symptoms should be evaluated
and NORVIR therapy should be discontinued if a diagnosis of pancreatitis
is made.<br/>Diabetes Mellitus/Hyperglycemia: New onset diabetes
mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia
have been reported during postmarketing surveillance in HIV-infected
patients receiving protease inhibitor therapy. Some patients required
either initiation or dose adjustments of insulin or oral hypoglycemic
agents for treatment of these events. In some cases, diabetic ketoacidosis
has occurred. In those patients who discontinued protease inhibitor
therapy, hyperglycemia persisted in some cases. Because these events
have been reported voluntarily during clinical practice, estimates
of frequency cannot be made and a causal relationship between protease
inhibitor therapy and these events has not been established.
|
| dailymed-instance:indicatio... |
NORVIR is indicated in combination
with other antiretroviral agents for the treatment of HIV-infection.
This indication is based on the results from a study in patients
with advanced HIV disease that showed a reduction in both mortality
and AIDS-defining clinical events for patients who received NORVIR
either alone or in combination with nucleoside analogues. Median
duration of follow-up in this study was 13.5 months.<br/>Description of Clinical Studies: The activity of
NORVIR as monotherapy or in combination with nucleoside reverse transcriptase
inhibitors has been evaluated in 1446 patients enrolled in two double-blind,
randomized trials.<br/>Advanced Patients with Prior Antiretroviral Therapy: Study 247
was a randomized, double-blind trial (with open-label follow-up) conducted
in HIV-infected patients with at least nine months of prior antiretroviral
therapy and baseline CDcell counts���100 cells/��L.
NORVIR 600 mg twice-daily or placebo was added to each patient's
baseline antiretroviral therapy regimen, which could have consisted
of up to two approved antiretroviral agents. The study accrued 1090
patients, with mean baseline CDcell count at study entry
of 32 cells/��L. After the clinical benefit of NORVIR therapy
was demonstrated, all patients were eligible to switch to open-label
NORVIR for the duration of the follow-up period. Median duration
of double-blind therapy with NORVIR and placebo was 6 months. The
median duration of follow-up through the end of the open-label phase
was 13.5 months for patients randomized to NORVIR and 14 months
for patients randomized to placebo. The cumulative incidence of clinical disease
progression or death during the double-blind phase of Study 247 was
26% for patients initially randomized to NORVIR compared to 42% for
patients initially randomized to placebo. This difference in rates
was statistically significant (see Figure 1). The cumulative
mortality through the end of the open-label follow-up phase for patients
enrolled in Study 247 was 18% for patients initially randomized to
NORVIR compared to 26% for patients initially randomized to placebo.
This difference in rates was statistically significant (see Figure
2). Since the analysis at the end of the open-label phase includes
patients in the placebo arm who were switched from placebo to NORVIR
therapy, the survival benefit of NORVIR cannot be precisely estimated. Figure 3 and
Figure 4 summarize the mean change from baseline for CDcell count and plasma HIV RNA (copies/mL), respectively, during
the first 24 weeks for the double-blind phase of Study 247.<br/>Patients Without Prior Antiretroviral Therapy: In Study
245, 356 antiretroviral-naive HIV-infected patients (mean baseline
CD= 364 cells/��L) were randomized
to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily,
or a combination of these drugs. Figure 5 and Figure 6 summarize
the mean change from baseline for CDcell count and plasma
HIV RNA (copies/mL), respectively, during the first 24 weeks for the
double-blind phase of Study 245.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
NORVIR
|