Lopinavir

628.8

628.80

740137

DTXSID8046456

Colorless solid from ethyl acetone|White to light tan powder

29335990

120.00000

4.39310

white to beige

1.163±0.06 g/cm3(Predicted)

124-127°C

924.1±65.0 °C(Predicted)

512.7±34.3 °C

1.577

DMSO: soluble20mg/mL, clear

Hygroscopic, -20°C Freezer, Under inert atmosphere

0mmHg at 25°C

Henry's law constant = 4.3X10-28 atm-cu m/mol at 25 °C (est)

3077

Xi

Hygroscopic

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including lopinavir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H315 (90%): Causes skin irritation [Warning Skin corrosion/irritation]|P260, P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P314, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 61 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Respiratory Protection: Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used. Gloves: Chemically compatible Eye Protection: Safety glasses or goggles Protective Clothing: Protect exposed skin.|Engineering controls such as exhaust ventilation are recommended.

This material is assumed to be combustible.

Extinguisher Media: Water spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials. ... Firefighting Procedures: As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves. Measures for cleaning/collecting: absorb solutions with finely- powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, federal, state and local regulations/.|Spill Response: Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site.

As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.|As with all dry powders, it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.|Handling should only be performed by personnel trained and familiar with handling of potent active pharmaceutical ingredients.

Some degree of serum aminotransferase elevations occur in a high proportion of patients taking lopinavir containing antiretroviral regimens. Moderate-to-severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Clinically apparent liver disease due to lopinavir/ritonavir occurs, but is rare. The latency to onset of symptoms or jaundice is usually 1 to 8 weeks and the pattern of serum enzyme elevations varies from hepatocellular to cholestatic or mixed. The injury is usually self-limited; however, fatal cases have been reported. In addition, initiation of lopinavir/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 in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Lopinavir 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.

Possible pharmacokinetic interaction with amiodarone, bepridil (no longer commercially available in the US), lidocaine (systemic), and quinidine (increased plasma concentrations of the antiarrhythmic agent). Use with caution. Monitor plasma concentrations of the antiarrhythmic agents if used concomitantly with lopinavir/ritonavir.|Pharmacokinetic interaction (increased alfuzosin plasma concentrations) may result in hypotension. Concomitant use of lopinavir/ritonavir and alfuzosin is contraindicated.|Lopinavir/ritonavir induces glucuronidation (i.e., increases biotransformation of some drugs metabolized by glucuronidation).|The fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) inhibits the cytochrome P-450 (CYP) isoenzyme; potential pharmacokinetic interactions with drugs metabolized by CYP3A (altered metabolism of the drug metabolized by CYP3A). Concomitant use with some drugs that are CYP3A substrates is contraindicated; concomitant use with other drugs that are CYP3A substrates may require dosage adjustment or additional monitoring. Lopinavir and ritonavir are metabolized by CYP3A; potential pharmacokinetic interactions with drugs that inhibit or induce CYP3A (altered metabolism of lopinavir).|For more Interactions (Complete) data for Lopinavir (61 total), please visit the HSDB record page.

Lopinavir's production and administration in the antiretroviral drug Kaletra(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+6(SRC), determined from a structure estimation method(2), indicates that lopinavir is expected to be immobile in soil(SRC). Volatilization of lopinavir from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.3X10-28 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Lopinavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.4X10-24 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2013).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+6(SRC), determined from a structure estimation method(2), indicates that lopinavir is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.3X10-28 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 2200(SRC), from an estimated log Kow of 5.94(6) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is very high, provided the compound is not metabolized by the organism(SRC). Biodegradation data in water were not available(SRC, 2013).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), lopinavir, which has an estimated vapor pressure of 3.4X10-24 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase lopinavir may be removed from the air by wet and dry deposition(SRC). Lopinavir does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Lopinavir is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Lopinavir does not contain chromophores that absorb at wavelengths >290 nm(1) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 2200 was calculated in fish for lopinavir(SRC), using an estimated log Kow of 5.94(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of lopinavir can be estimated to be 1.0X10+6(SRC). According to a classification scheme(2), this estimated Koc value suggests that lopinavir is expected to be immobile in soil.

The Henry's Law constant for lopinavir is estimated as 4.3X10-28 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that lopinavir is expected to be essentially nonvolatile from water and moist surfaces(2). Lopinavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.4X10-24 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to lopinavir were not located(SRC, 2013), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are, therefore, discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Occupational exposure to lopinavir may occur through inhalation and dermal contact with this compound at workplaces where lopinavir is produced or used. Exposure to lopinavir among the general population may be limited to those administered the drug Kaletra, an antiviral. (SRC)

Lopinavir is an antiretroviral protease inhibitor used in combination with ritonavir in the therapy and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Lopinavir can cause transient and usually asymptomatic elevations in serum aminotransferase levels and, rarely, clinically apparent, acute liver injury. In HBV or HCV coinfected patients, highly active antiretroviral therapy with lopinavir may result of an exacerbation of the underlying chronic hepatitis B or C.

Antiviral Agents

Anti-HIV Agents; HIV Protease Inhibitors|The fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients 14 days of age and older. Lopinavir/ritonavir is used in patients who are antiretroviral naive (have not previously received antiretroviral therapy) or antiretroviral experienced (received prior antiretroviral therapy). /Included in US product label/|The manufacturer advises that the following factors be considered when initiating lopinavir/ritonavir. Administration of lopinavir/ritonavir in conjunction with other active antiretroviral agents is associated with a greater likelihood of treatment response. Use of lopinavir/ritonavir should be guided by results of genotypic or phenotypic viral resistance testing and/or the individual's prior antiretroviral treatment. The number of lopinavir resistance-associated mutations at baseline affects virologic response to lopinavir/ritonavir. Once-daily administration of lopinavir/ritonavir is not recommended in adults infected with HIV-1 strains with 3 or more viral mutations associated with lopinavir resistance and is not recommended in pediatric patients.|Lopinavir/ritonavir is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection in individuals who have had nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission. /NOT included in US product label/|For more Therapeutic Uses (Complete) data for Lopinavir (6 total), please visit the HSDB record page.

Serious and/or life-threatening adverse effects, clinically important drug interactions, or loss of virologic effect can occur if the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) is used concomitantly with some drugs. The potential for drug interactions must be considered prior to and during lopinavir/ritonavir therapy. Clinicians should review all drugs the patient is receiving and should monitor for adverse effects during lopinavir/ritonavir therapy.|Lopinavir/ritonavir oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol. When administered concomitantly with propylene glycol, ethanol competitively inhibits metabolism of propylene glycol, which may lead to elevated propylene glycol concentrations. Preterm neonates /NOT included in US product label/may be at increased risk of propylene glycol-associated adverse effects due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Life-threatening cardiac toxicity (including complete atrioventricular [AV] block, bradycardia, cardiomyopathy), lactic acidosis, acute renal failure, CNS depression, and respiratory complications leading to death have been reported, predominantly in preterm neonates /NOT included in US product label/ receiving lopinavir/ritonavir oral solution. Neonates, especially those born prematurely, are at risk of lopinavir, ethanol, and/or propylene glycol toxicity if they receive lopinavir/ritonavir oral solution.|Once-daily regimens of lopinavir/ritonavir have not been evaluated in pediatric patients, and are not recommended in patients younger than 18 years of age.|A safe and effective dose of lopinavir/ritonavir oral solution has not been established in neonates younger than 14 days of age /NOT included in US product label/ (whether born prematurely or full term). If the benefits of the oral solution for the treatment of HIV infection in an infant immediately after birth are judged to outweigh potential risks, the infant should be monitored closely for increases in serum osmolality and serum creatinine and other signs of toxicity related to the oral solution. These toxicities include hyperosmolality with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, apnea), seizures, hypotonia, cardiac arrhythmias, ECG changes, and hemolysis. If lopinavir/ritonavir oral solution is used in preterm neonates /NOT included in US product label/ or in pediatric patients 14 days to 6 months of age, total amounts of alcohol and propylene glycol from all drugs that the child is receiving should be taken into account to avoid toxicity associated with these excipients.|For more Drug Warnings (Complete) data for Lopinavir (19 total), please visit the HSDB record page.

The clinical relevance of reduced in vitro susceptibility to lopinavir was examined by assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing therapy with multiple protease inhibitors. The EC50 of lopinavir against the 56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV. After 24 weeks of treatment with lopinavir/ritonavir in combination with efavirenz + Nucleoside Reverse Transcriptase Inhibitors (NRTIs), the response rate diminished in patients who had 10 to 20-fold and 20 to 40-fold reduced susceptibility to lopinavir at baseline (78% and 67% respectively in comparison to 93 % in patients with < 10-fold reduced susceptibility to lopinavir at baseline). A substantial response rate of 50 % was even observed among patients with baseline isolates > 40-fold reduced in vitro susceptibility to lopinavir. Virologic response was also related to baseline genotype. In particular a high response rate (24/25; 96%) was observed in patients whose baseline isolates contained 5 or less of the 11 mutations associated with reduced in vitro susceptibility to lopinavir compared to the response rate (2/6; 33%) observed in patients whose baseline isolates contained 8 or more mutations.|The in vitro antiviral activity of lopinavir was assessed against a panel of 112 clinical isolates obtained from patients failing protease inhibitors therapy (patients from studies M97-765 and M98-957). The following eleven amino acid positions in HIV protease were found to be statistically correlated with reduced in vitro susceptibility to lopinavir: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M. The median EC50 of lopinavir against these isolates with 0-3, 4-5 6-7 and 8-10 mutations at the above amino acid positions was 0.8, 2.7, 13.5 and 44.0-fold higher than the EC50 against the wild type, respectively. The 16 viruses that displayed > 20-fold change in susceptibility contained all mutations at positions 10, 54, 63 plus 82 and/or 84. In addition, they had a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90.|Lopinavir (LPV) is a second generation HIV-1 protease inhibitor. Drug resistance has rapidly emerged against LPV since its US FDA approval on September 15, 2000. Mutations at residues 32I, L33F, 46I, 47A, I54V, V82A, I84V, and L90M render the protease drug resistant against LPV. /The investigators/ report the crystal structure of a clinical isolate multi-drug resistant (MDR) 769 HIV-1 protease (resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90) complexed with LPV and the in vitro enzymatic IC50 of LPV against MDR 769. The structural and functional studies demonstrate significant drug resistance of MDR 769 against LPV, arising from reduced interactions between LPV and the protease target.

At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg KALETRA twice daily, and is similar between healthy volunteers and HIV-1 positive patients.|In a pharmacokinetic study in HIV-1 positive subjects (n = 19), multiple dosing with 400/100 mg KALETRA twice daily with food for 3 weeks produced a mean SD lopinavir peak plasma concentration (Cmax) of 9.8 + or - 3.7 ug/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 + or - 2.9 ug/mL and minimum concentration within a dosing interval was 5.5 + or - 2.7 ug/mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 + or - 36.7 ug*h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the KALETRA oral solution relative to the capsule formulation.|Lopinavir and ritonavir are distributed into milk in rats; it is not known whether the drugs are distributed into human milk.|The pharmacokinetics of once daily Kaletra have been evaluated in HIV-1 infected subjects naive to antiretroviral treatment. Kaletra 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once daily regimen. Multiple dosing of 800/200 mg Kaletra once daily for 4 weeks with food (n = 24) produced a mean + or - 3.7 SD lopinavir peak plasma concentration (Cmax) of 11.8 + or - 3.7 ug/mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 + or - 3.7 2.1 ug/mL and minimum concentration within a dosing interval was 1.7 + or - 3.7 1.6 ug/mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 + or - 3.7 61.4 ug* h/mL.|For more Absorption, Distribution and Excretion (Complete) data for Lopinavir (11 total), please visit the HSDB record page.

Lopinavir was metabolised in rat, dog and human primarily by hepatic CYP3A4 isoenzymes. Radioactivity in rat and dog faeces consisted largely of unchanged parent compound after oral administration. Although there were similarities in metabolite pattern between rat, dog and human, qualitative and quantitative differences were observed. The metabolism of lopinavir was sensitive to inhibition of ritonavir, which is in accordance with the inhibition of metabolic clearance of lopinavir by ritonavir observed in the rat.|In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A (14)C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.

After single dose administration, mean elimination half-life ranged between 2 to 3 hours and seemed to be increased after multiple dose administration (about 4-6 hr).

/The researchers/ have previously shown that the HIV protease inhibitor lopinavir has selective toxicity against human papillomavirus (HPV)-positive cervical carcinoma cells via an unknown mechanism. SiHa cervical carcinoma cells were stably transfected with the proteasome sensor vector pZsProSensor-1 to confirm lopinavir inhibits the proteasome in these cells. The Panorama Xpress profiler 725 antibody array was then used to analyse specific changes in protein expression in lopinavir-treated versus control untreated SiHa cells followed by PCR and western blotting. Colorimetric growth assays of lopinavir-treated E6/E7 immortalised versus control human keratinocytes were performed. Targeted small interfering RNA gene silencing followed by growth assay comparison of lopinavir-treated/untreated SiHa cells was also used. Lopinavir induced an increase in the fluorescence of pZsProSensor-1 transfected SiHa cells, indicative of proteasomal inhibition. Ribonuclease L (RNASEL) protein was shown to be up-regulated in lopinavir-treated SiHa cells, which was confirmed by PCR and western blot. Targeted silencing of RNASEL reduced the sensitivity of SiHa cells to lopinavir. Selective toxicity against E6/E7 immortalised keratinocytes versus control cells was also seen with lopinavir and was associated with up-regulated RNASEL expression. These data are consistent with the toxicity of lopinavir against HPV-positive cervical carcinoma cells being related to its ability to block viral proteasome activation and induce an up-regulation of the antiviral protein RNASEL. This is supported by the drug's selective toxicity and up-regulation of RNASEL in E6/E7 immortalised keratinocytes combined with the increased resistance to lopinavir observed in SiHa cells following silencing of RNASEL gene expression.|Lopinavir inhibits replication of HIV type 1 (HIV-1) by interfering with HIV protease. During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes to form structural proteins of the virion core and essential viral enzymes. By interfering with the formation of these essential proteins and enzymes, lopinavir blocks maturation of the virus and causes formation of nonfunctional, immature, noninfectious virions. Lopinavir also has some in vitro activity against HIV type 2 (HIV-2).

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). 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 0.9% saline (NS) 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 ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Emergency and supportive measures: 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. /Antiviral and antiretroviral agents/|For more Antidote and Emergency Treatment (Complete) data for Lopinavir (6 total), please visit the HSDB record page.

/CASE REPORTS/ A French Caucasian man aged 39 with HIV infection was treated with abacavir/lamivudine and ritonavir/lopinavir. The patient (normal renal and liver functions) was diagnosed with a Burkitt lymphoma for which he was treated with cyclophosphamide day 1 to 5; doxorubicin day 1; methotrexate day 10; and vincristine day 1 and 8. At day 12, he suffered from abdominal pain associated with constipation. Paralytic ileus was diagnosed by study imaging. Ileus lasted 10 days necessitating parenteral feeding. Later on, a further cycle of chemotherapy with etoposide replacing vincristine was given and was well tolerated. /The researchers/ speculate that an interaction between ritonavir/lopinavir and vincristine was responsible for this severe toxicity. Vincristine is transported by P-gp and is metabolized via CYP3A5. Ritonavir is a potent CYP3A5 isoenzyme and P-gp inhibitor. Lopinavir is also a P-gp inhibitor. Ritonavir and lopinavir might have delayed vincristine elimination. Clinicians should be aware of this possible interaction.|/CASE REPORTS/ /The investigators/ report twin neonates who were born prematurely at 32 weeks of gestation to a mother with human immunodeficiency virus infection. One of the twins developed complete heart block and dilated cardiomyopathy related to lopinavir/ritonavir therapy, a boosted protease-inhibitor agent, while the other twin developed mild bradycardia. /The investigators/ recommend caution in the use of lopinavir/ritonavir in the immediate neonatal period.|/CASE REPORTS/ One death has occurred as a result of inadvertent overdosage of lopinavir/ritonavir oral solution. This overdose occurred in a 44-day-old HIV-infected infant given approximately 6.5 mL of lopinavir/ritonavir oral solution (10 times the calculated dose). The infant died 9 days later of cardiogenic shock. To avoid medication errors and minimize the risk for overdosage when the oral solution is used, extra care should be taken to ensure the accuracy of the prescription.|/EPIDEMIOLOGY STUDIES/ Lopinavir-ritonavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor boosted by ritonavir, a cytochrome p450 inhibitor. A warning about its tolerance in premature newborns was recently released, and transient elevation of 17-hydroxyprogesterone (17OHP) was noted in 2 newborns treated with lopinavir-ritonavir in France. To evaluate adrenal function in newborns postnatally treated with lopinavir-ritonavir, a retrospective cross-sectional analysis of the database from the national screening for congenital adrenal hyperplasia (CAH) and the French Perinatal Cohort /was performed/. Comparison of HIV-1-uninfected newborns postnatally treated with lopinavir-ritonavir and controls treated with standard zidovudine. Plasma 17OHP and dehydroepiandrosterone-sulfate (DHEA-S) concentrations during the first week of treatment. Clinical and biological symptoms compatible with adrenal deficiency. RESULTS: Of 50 HIV-1-uninfected newborns who received lopinavir-ritonavir at birth for a median of 30 days (interquartile range [IQR], 25-33), 7 (14%) had elevated 17OHP levels greater than 16.5 ng/mL for term infants (>23.1 ng/mL for preterm) on days 1 to 6 vs 0 of 108 controls having elevated levels. The median 17OHP concentration for 42 term newborns treated with lopinavir-ritonavir was 9.9 ng/mL (IQR, 3.9-14.1 ng/mL) vs 3.7 ng/mL (IQR, 2.6-5.3 ng/mL) for 93 term controls (P < .001). The difference observed in median 17OHP values between treated newborns and controls was higher in children also exposed in utero (11.5 ng/mL vs 3.7 ng/mL; P < .001) than not exposed in utero (6.9 ng/mL vs 3.3 ng/mL; P = .03). The median DHEA-S concentration among 18 term newborns treated with lopinavir-ritonavir was 9242 ng/mL (IQR, 1347-25,986 ng/mL) compared with 484 ng/mL (IQR, 218-1308 ng/mL) among 17 term controls (P < .001). The 17OHP and DHEA-S concentrations were positively correlated (r = 0.53; P = .001). All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment. Among newborn children of HIV-1-infected mothers exposed in utero to lopinavir-ritonavir, postnatal treatment with a lopinavir-ritonavir-based regimen, compared with a zidovudine-based regimen, was associated with transient adrenal dysfunction.

Table: Lopinavir and Ritonavir Preparations [Table#8113]