WarningH302+H312+H332 (41.7%): Harmful if swallowed, in contact with skin or if inhaled [Warning Acute toxicity, oralacute toxicity, dermalacute toxicity, inhalation]P203, P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P318, P321, P330, P337+P317, P362+P364, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 96 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
FDA-Anforderungen
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl ritonavir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
Hazard Classes and Categories
Acute Tox. 4 (88.5%)
Lagerbedingungen
Commercially available ritonavir oral solution should be stored at room temperature at 20-25Cthe oral solution should not be refrigerated. Exposure to excessive heat should be avoided. Ritonavir oral solution should be stored in the manufacturer-provided amber bottle and protected from light.Ritonavir liquid-filled (soft gelatin) capsules should be refrigerated at 28 °C until dispensed. Once dispensed, the liquid-filled capsules should be refrigerated, but may be stored at a temperature lower than 25 °C for up to 30 days. The capsules should be protected from light and excessive heat.
Entsorgungsverfahren
SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air qualitypotential migration in soil or watereffects on animal, aquatic, and plant lifeand conformance with environmental and public health regulations.
Wechselwirkungen
These medications /amiodarone, astemizole, bepridil, bupropion, cisapride, clozapine, dihydroergotamine, encainide, ergotamine, flecainide, meperidine, pimozide, piroxicam, propafenone, propoxyphene, quinidine, rifabutin or terfenadine/ should not be administered concurrently with ritonavir
Anwendungen & Verwendung
Beschreibung
Ritonavir (brand name: Norvir) was launched in Germany, the UK and US for treatment of advanced HIV in combination with antiretroviral nucleoside analogs in a record 72 days by the FDA. It is an inhibitor of HIV aspartic protease which is critical in the processing of a propeptide into the gag, gag-pol gene products and the protease itself. This inhibition results in the release of non-infectous immature virus particles. It is greater than 500-fold more selective for viral aspartic protease than the human version, has good oral bioavailability and may increase the bioavailability of other protease inhibitors. Ritonavir was able to increase the CD4 and CD8 lymphocyte count as well as reduce viral RNA. It is more potent than saqunavir and comparible in potency to zidovudine and lamivudine.
History
Ritonavir is an antiretroviral drug discovered by Abbott Laboratories to treat acquired immunodeficiency syndrome (AIDS). It was approved by the Food and Drug Administration (FDA) in 1996, and was marketed in semi-solid capsule form under the brand name Norvir. Although it was originally developed for use as a protease inhibitor in a three-drug combination, today ritonavir is used in low doses to boost the effect (blood levels) of one of the other protease inhibitors.
Verwenden
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients. Ritonivir is an HIV protease inhibitor (EC50 = 25 nM) that also inhibits CYP3A4, the primary cytochrome P450 isoform that metabolizes protease inhibitors. Through CYP3A4 inhibition, low doses of ritonivir can reduce the metabolism of concomitantly administered protease inhibitiors, enhancing their bioavailability and efficacy.
concurrent administration with ritonavir is likely to produce a large increase in the plasma concentrations of these medications, which may increase the risk of arrhythmias, hematologic abnormalities, seizures, or other potentially serious adverse effects.
In one study, concurrent administration /with clarithromycin/ increased the AUC of clarithromycin by 77% and the peak plasma concentration by 31%
dosing does not need to be adjusted in patients with normal renal function
however, for patients with a creatinine clearance of 30 to 60 ml/minute (0.5 to 1 ml/second), the dose of clarithromycin should be reduced by 50%, and for patients with a creatinine clearance of less than 30 ml/minute (0.5 ml/second), the dose of clarithromycin should be reduced by 75%.
These medications /clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, or zolpidem/ should not be administered concurrently with ritonavir
concurrent administration with ritonavir is likely to produce a large increase in the plasma concentrations of these medications, which may produce extreme sedation and respiratory depression.
In one study, concurrent administration /with estrogen-containing oral contraceptive/ decreased the AUC of ethinyl estradiol by 40%
an oral contraceptive with a higher estrogen content or an alternative method of contraception should be considered.
For more Interactions (Complete) data for RITONAVIR (14 total), please visit the HSDB record page.
Hepatotoxicity
Some degree of serum aminotransferase elevations occurs in a high proportion of patients taking ritonavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in up to 15% of patients treated with full doses of ritonavir and are more common in patients with HIV-HCV coinfection. With low “booster” doses, ritonavir does not appear to increase the frequency or severity of serum enzyme elevations, and those that occur are usually asymptomatic and self-limited, resolving even with continuation of ritonavir. Clinically apparent liver injury from full doses of ritonavir has been reported, but hepatotoxicity from low dose ritonavir has not been clearly linked to acute liver injury. In many situations, the liver injury is difficult to attribute to ritonavir because it is used in combination with higher doses of other protease inhibitors. HIV protease inhibitors have been associated with acute liver injury arising 1 to 8 weeks after onset, with variable patterns of liver enzyme elevation, from hepatocellular to cholestatic. Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. Ritonavir in combination with saquinavir has also been associated with a rapid onset (1 to 4 days) acute hepatic injury in patients who are taking rifampin and perhaps other agents that affect CYP 450 activity, such as phenobarbital. Finally, initiation of ritonavir based highly active antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy and associated with a hepatocellular pattern of serum enzyme elevations and increases followed by falls in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Ritonavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.
Unerwünschte Wirkungen
Ritonavir has several constitutional side effects, including malaise, dizziness, and insomnia, gastrointestinal side effects including nausea, vomiting, abdominal pain, and diarrhea, and metabolic side effects such as hyperlipidemia, hypertriglyceridemia, transaminitis, and rhabdomyolysis. Although there are reports of QT prolongation with the use of protease inhibitors, studies have not established them as independent culprits.
Toxizitätsübersicht
Because there is a small quantity of ritonavir in the combination of lopinavir/ritonavir, there are few reports of ritonavir toxicity. However, a few case reports have suggested retinal toxicity secondary to ritonavir. One such case showed an improvement after discontinuing ritonavir after 2 and 4 weeks.
Human Toxicity Excerpts
/HUMAN EXPOSURE STUDIES/ Overdosage of ritonavir would be expected to produce manifestations that are principally extensions of the adverse reactions reported with the drug. Paresthesia occurred in one patient who ingested 1.5 g of ritonavir daily for 2 daysthis adverse effect resolved once the ritonavir dosage was decreased. Renal failure with eosinophilia has occurred in association with an overdosage of ritonavir./HUMAN EXPOSURE STUDIES/ Hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, or liver damage have been reported in less than 2% of patients receiving ritonavir in clinical studies. There have been postmarketing reports of hepatic dysfunction, including some fatalities, in patients receiving ritonavir. These generally occurred in patients receiving multiple drugs and/or with advanced AIDS./HUMAN EXPOSURE STUDIES/ Adverse hematologic effects reported in less than 2% of patients receiving ritonavir alone or with other antiretroviral agents include anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder, and thrombocytopenia./HUMAN EXPOSURE STUDIES/ Pancreatitis, including some fatalities, has been reported in patients receiving ritonavir, including some patients who developed hypertriglyceridemia. Pancreatitis has been reported in less than 2% of patients receiving ritonavir in clinical studies. Fatal pancreatitis has been reported in a few patients receiving didanosine, stavudine, and an HIV protease inhibitor (i.e., indinavir, nelfinavir). Pancreatorenal syndrome consisting of acute pancreatitis in conjunction with acute renal failure has been reported in at least one patient receiving a multiple-drug regimen that included ritonavirthis syndrome also has been reported rarely in patients receiving regimens that did not include ritonavir.For more Human Toxicity Excerpts (Complete) data for RITONAVIR (9 total), please visit the HSDB record page.
Drug Induced Liver Injury
Drug Induced Liver Injury Rank (DILIrank 2.0)RitonavirvMost-DILI-concern8Warnings & precautionsDOI:10.1016/j.drudis.2016.02.015
Non-Human Toxicity Excerpts
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rats or rabbits at ritonavir exposure levels calculated to be equivalent to or twice the usual human dosage, respectively, did not reveal evidence of embryotoxicity or teratogenicity. In rats, developmental toxicity (i.e., early resorptions, decreased fetal body weight, ossification delays, developmental variations) occurred at a maternally toxic dosage (i.e., ritonavir exposure level equivalent to 30% of that attained with the usual human dosage)a slight increase in the incidence of cryptorchidism was observed in rats at a ritonavir exposure level equivalent to 22% of that achieved with the usual human dosage. In rabbits, developmental toxicity (i.e., resorptions, decreased litter size, decreased fetal body weight) occurred at a maternally toxic dosage (i.e., ritonavir exposure level equivalent to 1.8 times that attained with the usual human dosage based on a body surface area conversion factor)./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ There was no evidence that ritonavir affected fertility when the drug was given to male or female rats at exposure levels equivalent to 40 or 60%, respectively, of those expected with the usual human dosage. Higher ritonavir doses were not studied in these animals due to hepatic toxicity./GENOTOXICITY/ Ritonavir was not mutagenic or clastogenic in vitro and in vivo studies, including bacterial reverse mutation (Ames) assays using Salmonella typhimurium and Escherichia coli, the mouse lymphoma cell test, and the mouse micronucleus assay.
Antidote and Emergency Treatment
To enhance elimination: Administration of activated charcoal. Monitoring: Monitoring of vital signs and observation of the clinical status of the patient. Supportive care: Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/Treatment of overdose: To decrease absorption: Patients may benefit from treatment with activated charcoal. Monitoring: Patient's vital signs should be monitored. Supportive care: Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.Maintain an open airway and assist ventilation if needed. Treat coma, seizures, hypotension or anaphylaxis if they occur. replace fluid losses resulting from gastroenteritis with intravenous crystalloids. Maintain steady urine flow with intravenous fluids to alleviate crystalluria and reverse renal dysfunction. Treat lactic acidosis with judicious doses of sodium bicarbonate and by withdrawal of the offending drug. There are no specific antidotes for these agents. Administer activated charcoal.
