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Norvir

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Norvir

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including important WARNINGS AND PRECAUTIONS.

Drug Interactions

NORVIR is a CYP3A inhibitor. Initiating treatment with NORVIR in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already maintained on NORVIR may result in increased plasma concentrations of concomitant medications. Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. The potential for drug-drug interactions must be considered prior to and during therapy with NORVIR. Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with NORVIR.

See Table 2 for a listing of drugs that are contraindicated with NORVIR due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. Also, see Table 5 for a listing of drugs with established and other significant drug interactions [see CONTRAINDICATIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Toxicity in Preterm Neonates

NORVIR oral solution contains the excipients alcohol (43.2% v/v) and propylene glycol (26.57% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at an increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving lopinavir/ritonavir oral solution which also contains the excipients alcohol and propylene glycol.

NORVIR oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using NORVIR oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to NORVIR oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients [see DOSAGE AND ADMINISTRATION and OVERDOSAGE].

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 4). 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 [see Use In Specific Populations].

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.

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.

Allergic Reactions/Hypersensitivity

Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. Discontinue treatment if severe reactions develop.

PR Interval Prolongation

Ritonavir prolongs the PR interval in some patients. Post marketing cases of second or third degree atrioventricular block have been reported in patients.

NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Lipid Disorders

Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides [see ADVERSE REACTIONS]. Triglyceride and cholesterol testing should be performed prior to initiating NORVIR therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with NORVIR and HMG CoA reductase inhibitors [see CONTRAINDICATIONS and DRUG INTERACTIONS].

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.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

Resistance/Cross-resistance

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology].

Laboratory Tests

Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION)

Information For Patients

Patients or parents of patients should be informed that:

General Information
  • They should pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of NORVIR.
  • They should inform their healthcare provider if their children's weight changes in order to make sure that the child's NORVIR dose is the correct one.
  • Take NORVIR with meals.
  • For adult patients taking NORVIR tablets, the maximum dose of 600 mg twice daily by mouth with meals should not be exceeded.
  • Patients should remain under the care of a physician while using NORVIR. Patients should be advised to take NORVIR and other concomitant antiretroviral therapy every day as prescribed. NORVIR must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of NORVIR is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.
  • NORVIR is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using NORVIR.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
  • Do not breastfeed. We do not know if NORVIR can be passed to the baby through breast milk and whether it could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
  • Sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death.
Drug Interactions
  • NORVIR may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's Wort.
  • If they are receiving estrogen-based hormonal contraceptives, additional or alternate contraceptive measures should be used during therapy with NORVIR.
Potential Adverse Effects
  • Pre-existing liver disease including Hepatitis B or C can worsen with use of NORVIR. This can be seen as worsening of transaminase elevations or hepatic decompensation. Patients should be advised that their liver function tests will need to be monitored closely especially during the first several months of NORVIR treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin.
  • Pancreatitis, including some fatalities, has been observed in patients receiving NORVIR therapy. Your patients should let you know of signs and symptoms (nausea, vomiting, and abdominal pain) that might be suggestive of pancreatitis.
  • Skin rashes ranging in severity from mild to Stevens-Johnson syndrome have been reported in patients receiving NORVIR. Patients should be advised to contact their healthcare provider if they develop a rash while taking NORVIR. The healthcare provider will determine if treatment should be continued or an alternative antiretroviral regimen used.
  • NORVIR may produce changes in the electrocardiogram (e.g., PR prolongation). Patients should consult their physician if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness.
  • Treatment with NORVIR therapy can result in substantial increases in the concentration of total cholesterol and triglycerides.
  • New onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported. Patients should be advised to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on NORVIR as they may require a change in their diabetes treatment or new treatment.
  • Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR.
  • Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.
  • Patients with hemophilia may experience increased bleeding when treated with protease inhibitors such as NORVIR.
  • If they are receiving avanafil, sildenafil, tadalafil, or vardenafil for the treatment of erectile dysfunction, they may be at an increased risk of associated adverse reactions including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor. They should seek medical assistance immediately if they develop a sustained penile erection lasting more than 4 hours while taking NORVIR and a PDE 5 Inhibitor such as Stendra®, Viagra®, Cialis®or Levitra®. If they are currently using or planning to use avanafil or tadalafil (for the treatment of pulmonary arterial hypertension) they should ask their doctor about potential adverse reactions these medications may cause when taken with NORVIR. The doctor may choose not to keep them on avanafil, or may adjust the dose of tadalafil while initiating treatment with NORVIR. Concomitant use of Revatio®(sildenafil) with NORVIR is contraindicated in patients with pulmonary arterial hypertension (PAH).
  • Continued NORVIR therapy at a dose of 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg per kg per day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice-daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg per kg per day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.

Mutagenesis

However, ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Impairment of Fertility

Ritonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity.

Use In Specific Populations

When co-administering NORVIR with other protease inhibitors, see the full prescribing information for the co-administered protease inhibitor including important information for use in special populations.

Pregnancy

Pregnancy Category B
Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to NORVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1–800–258–4263.

Human Data

There are no adequate and well-controlled studies in pregnant women. NORVIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

As of January 2012, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 3860 exposures to ritonavir containing regimens (1567 exposed in the first trimester and 2293 exposed in the second and third trimester). Birth defects occurred in 35 of the 1567 (2.2%) live births (first trimester exposure) and 59 of the 2293 (2.6%) live births (second/third trimester exposure).

Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between ritonavir and overall birth defects observed in the APR.

Animal Data

No treatment related malformations were observed when ritonavir was administered to pregnant rats or rabbits. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage at an exposure equivalent to approximately 30% of that achieved with the proposed therapeutic dose. A slight increase in the incidence of cryptorchidism was also noted in rats at an exposure approximately 22% of that achieved with the proposed therapeutic dose.

Developmental toxicity observed in rabbits (resorptions, decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage equivalent to 1.8 times the proposed therapeutic dose based on a body surface area conversion factor.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether ritonavir is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving NORVIR.

Pediatric Use

In HIV-infected patients age greater than 1 month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.

Geriatric Use

Clinical studies of NORVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

No dose adjustment of ritonavir is necessary for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, ritonavir is not recommended for use in patients with severe hepatic impairment [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 11/22/2013
This monograph has been modified to include the generic and brand name in many instances.

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