Quantitative Estimation of Lopinavir and Ritonavir in Tablets

Quantitative Estimation of Lopinavir and Ritonavir in Tablets by RP-HPLC Method

Jagadeeswaran M1 *, Gopal N2 , Pavan kumar K1 and Siva kumar T1.
1Nandha College of Pharmacy and Research Institute, Department of Pharmaceutical Analysis, Erode -638 052, Tamil Nadu, India 2Balaji Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Narsampet, Warangal-506 331, Andhra Pradesh, India

Notice:

Lopinavir and ritonavir are currently being studied in several ongoing clinical studies for the treatment of coronavirus disease 2019 (COVID-19) either alone or with other medications. The use of lopinavir and ritonavir for the treatment of COVID-19 has not yet been established. Some scientists are hopeful because these medications have been used to treat similar viral infections. Lopinavir and ritonavir should be taken ONLY under the direction of a doctor for the treatment of COVID-19.

Abstract  :- 

BACKGROUND

No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. A reversed phase high-performance liquid chromatographic method was developed and validated for the quantitative determination of two antiviral drugs viz. lopinavir and ritonavir. Chromatography was carried out by gradient technique on a reversed-phase C18 Column, Phenomenex (250 x 4.6 mm, 5 µ) with mobile phase mixture of Buffer: Acetonitrile (45:55 v/v) was used as a mobile phase and the pH was adjusted into 4.5 by using with O-phosphoric acid, at a flow rate of 1.2 ml/min. The UV range was detected at 240 nm for lopinavir and ritonavir respectively. The different analytical performance parameters such as linearity, precision, accuracy, specificity, limit of detection (LOD) and limit of quantification (LOQ) were determined according to International Conference on Harmonization ICH Q2B guidelines. The linearity of the calibration curves for each analyte in the desired concentration range is good (r2 >0.9). The recovery of the method was between 102.1% and 100.1% for lopinavir and ritonavir respectively. Hence the proposed method is highly sensitive, precise and accurate and it successfully applied for the reliable quantification of API content in the commercial formulations of lopinavir and ritonavir. 

METHODS

We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.

Keywords: Lopinavir; Ritonavir; UV spectrophotometry; RP-HPLC

Introduction:-

 One of the deadliest and unmanageable chronic health catastrophes is HIV/AIDS. It requires lifelong treatment with potent life saving essential drugs that include nucleoside reverse transcriptase inhibitors, non nucleoside reverse transcriptase inhibitors and protease inhibitors. Amongst these lopinavir and ritonavir drug combination is a protease inhibitor used as a second line regimen to treat patients with HIV [1]. Lopinavir (the active ingredient) is chemically designated as [1S-[1R*,(R*) 3R*, 4R*]]-N-[4-[[(2,6-dimethylphenoxy) acetyl]amino]-3 -hydroxy-5-phenyl-1-(phenylmethyl) pentyl] tetrahydro-alpha-(1-methylethyl)-2-oxo-1 (2H)-pyrimidineacetamide. 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*)]. Literature survey revealed several analytical methods for the determination of ritoavir and lopinavir in tablets, capsules, and syrups which employ techniques such as high-performance liquid chromatography (HPLC), Ultra performance liquid chromatography (UPLC), and high performance thin layer chromatography (HPTLC). In biological fluids, the active principles as well as their metabolites have been quantitatively determined by

HPLC with UV detection, LC/MS/MS, Spectroscopic method, Micellar electrokinetic chromatography method and Tandem mass spectrometry. The proposed method was optimized and validated in accordance with International Conference on Hormonization (ICH) guidelines. The aim of present work is to develop a simple, rapid, precise, accurate and selective reversed phase chromatographic method and to estimate the lopinavir and ritoavir in bulk and its solid dosage forms.

Materials and Methods

 Chemicals:-  The bulk drugs of lopinavir and ritonavir were obtained as gift samples from Abbott Laboratories Ltd, Guwahati, India. HPLC grade acetonitrile and ammonia were obtained from Sigma Aldrich (Switzerland). Combination tablets of Lopinavir 200 mg and Ritonavir 50 mg from abbott were purchased from local market. Milli-Q-Water was used in all experiments. All the solutions for analysis were prepared and analyzed freshly. 

Instrumentation and analytical conditions:-  Chromatography was performed using a shimadzu LC-10ATvp series, (Kyoto, Japan) equipped with SPD-10A UV-Vis detector. Data acquisition and processing was performed using chemistry station software (LC solution). The methods were conducted using a gradient reverse phase technique. The analytical conditions (mobile phase composition, flow rate and analytical wavelengths) for the two drugs have been summarized in Table 1. The mobile phases were prepared freshly, filtered through 0.45 µ membrane filter (Millipore, USA) and sonicated (Branson sonicator 3210, Germany) for 10 min before use in order to deaerate.

Preparation of standard and quality control solutions:-  Primary stock solutions of lopinavir (100 mg) and ritonavir (100 mg) were prepared in ultra pure water and further diluted with water to obtain working standards in the concentration range of 40–200 µg/ ml and 10-50 µg/ml for lopinavir and ritonavir respectively. Quality control (QC) samples were run with each batch of working standards in order to calculate the validation parameters. QC samples were prepared in ultra pure water spiked with analytes at different concentrations following the same procedure as for calibration standards, using a different primary stock. The samples were analyzed with reagent blanks. All the solutions were prepared in triplicates.

Results and Discussion 

RP-HPLC method:-  A RP-HPLC method was developed for two anti-retroviral drugs, which can be conveniently employed for routine quality control in pharmaceutical dosage forms. The chromatographic conditions were optimized in order to provide a good performance of the assay. The mobile phase for each drug was selected based on its polarity. Different ratios of Buffer: ACN combinations were tried for lopinavir and ritonavir and the fixed mobile phase. The optimization of flow rate is critical since the extent of longitudinal broadening is inversely related to flow rate of mobile phase. In either case of high or low flow rates, an ideal Gaussian curve of the peak is not obtained as the peak symmetry parameters are affected, i.e. asymmetry factor deviates from unity. The retention times of ritonavir and lopinavir were 4.323 and 5.650 min, respectively. The methods were specific as none of the excipients interfered with the analytes of interest. Hence, the methods

were suitably employed for assaying the commercial anti-retroviral individual formulations.

 Linearity:- Calibration curves were obtained from the peak area and concentration of the drug were subjected to regression analysis and correlation coefficients.The mean RP-HPLC area responses for ritonavir and lopinavir at different concentrations. As shown, the responses for the drug was strictly linear (r2 > 0.999) in the concentration range of 10-50 µg/ml for ritonavir and 40-200 µg/ml for lopinavir respectively. The slope and intercept for lopinavir was found to be 21201 and 10566 where as for ritonavir was found to be 15278 and 26980 respectively.

Accuracy and precision:-  Accuracy and precision were determined by elaboration of three standard calibration curves, two from the same day (intra-day) and third one from a different day (inter-day). The intra-day and inter-day precisions (% RSD) at different concentration levels were found to be less than 2%. Moreover the % RSD (less variation) showed good precision of the developed HPLC methods. The respective RP-HPLC area responses from the accuracy determination study. Recovery experiment was carried out by applying the standard addition method. Drug assay was performed in triplicate by spiking with equivalent amount of raw material into each volumetric flask for each spike level to get the concentrations of lopinavir and ritonavir equivalent to 80%, 100%, and 120% of the standard concentrations of lopinavir and ritonavir. The average percentage recovery of both the drugs was found to be within the limits and it is highly accurate.

LOQ and LOD:-  The LOD and LOQ were determined from the calculated standard deviations of each calibration standard and it was found to be 0.013 µg/ml and 0.465 µg/ml for lopinavir and ritonavir respectively. The calculated LOQ and LOD concentrations confirmed that the method is sensitive. 

Specificity:-  The developed method is specific as none of the excipients interfered with the analytes of interest. Hence, this method is suitably employed for assaying the commercial anti-retroviral individual formulations.

Conclusion:- The proposed RP-HPLC is simple, reliable and selective. It also provides satisfactory accuracy and precision with lower limits of detection and quantification. Moreover the shorter duration of analysis for lopinavir and ritonavir make these reported methods suitable for routine quantitative analysis in pharmaceutical dosage forms. The recoveries achieved are good by both the methods.

RESULTS

A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the standard-care group. Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir–ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.

Beginning in December 2019, a novel coronavirus, designated SARS-CoV-2, has caused an international outbreak of respiratory illness termed Covid-19. The full spectrum of Covid-19 ranges from mild, self-limiting respiratory tract illness to severe progressive pneumonia, multiorgan failure, and death. Thus far, there are no specific therapeutic agents for coronavirus infections. After the emergence of severe acute respiratory syndrome (SARS) in 2003, screening of approved drugs identified lopinavir, a human immunodeficiency virus (HIV) type 1 aspartate protease inhibitor, as having in vitro inhibitory activity against SARS-CoV, the virus that causes SARS in humans. Ritonavir is combined with lopinavir to increase its plasma half-life through the inhibition of cytochrome P450. An open-label study published in 2004 suggested, by comparison with a historical control group that received only ribavirin, that the addition of lopinavir–ritonavir (400 mg and 100 mg, respectively) to ribavirin reduced the risk of adverse clinical outcomes (acute respiratory distress syndrome [ARDS] or death) as well as viral load among patients with SARS. However, the lack of randomization and a contemporary control group and the concomitant use of glucocorticoids and ribavirin in that study made the effect of lopinavir–ritonavir difficult to assess. Similarly, lopinavir has activity, both in vitro and in an animal model, against Middle East respiratory syndrome coronavirus (MERS-CoV), and case reports have suggested that the combination of lopinavir–ritonavir with ribavirin and interferon alfa resulted in virologic clearance and survival. However, because convincing data about the efficacy of this approach in humans are lacking, a clinical trial (with recombinant interferon beta-1b) for MERS is currently under way (ClinicalTrials.gov number, 

To evaluate the efficacy and safety of oral lopinavir–ritonavir for SARS-CoV-2 infection, we conducted a randomized, controlled, open-label trial, LOTUS China (Lopinavir Trial for Suppression of SARS-Cov-2 in China), in adult patients hospitalized with Covid-19.

PATIENTS

Patients were assessed for eligibility on the basis of a positive reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay (Shanghai ZJ Bio-Tec or Sansure Biotech) for SARS-CoV-2 in a respiratory tract sample tested by the local Center for Disease Control (CDC) or by a designated diagnostic laboratory. Male and nonpregnant female patients 18 years of age or older were eligible if they had a diagnostic specimen that was positive on RT-PCR, had pneumonia confirmed by chest imaging, and had an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) (Pao2:Fio2) at or below 300 mg Hg. Exclusion criteria included a physician decision that involvement in the trial was not in the patient’s best interest, presence of any condition that would not allow the protocol to be followed safely, known allergy or hypersensitivity to lopinavir–ritonavir, known severe liver disease (e.g., cirrhosis, with an alanine aminotransferase level >5× the upper limit of the normal range or an aspartate aminotransferase level >5× the upper limit of the normal range), use of medications that are contraindicated with lopinavir–ritonavir and that could not be replaced or stopped during the trial period available with the full text of this article at NEJM.org); pregnancy or breast-feeding, or known HIV infection, because of concerns about the development of resistance to lopinavir–ritonavir if used without combining with other antiretrovirals. Patients who were unable to swallow received lopinavir–ritonavir through a nasogastric tube.

TRIAL DESIGN AND OVERSIGHT

This was an open-label, individually randomized, controlled trial conducted from January 18, 2020, through February 3, 2020 (the date of enrollment of the last patient), at Jin Yin-Tan Hospital, Wuhan, Hubei Province, China. Because of the emergency nature of the trial, placebos of lopinavir–ritonavir were not prepared. Eligible patients were randomly assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg, orally; freely provided by the national health authority) twice daily, plus standard care, or standard care alone, for 14 days. Standard care comprised, as necessary, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation (ECMO). To balance the distribution of oxygen support between the two groups as an indicator of severity of respiratory failure, randomization was stratified on the basis of respiratory support methods at the time of enrollment: no oxygen support or oxygen support with nasal duct or mask, or high-flow oxygen, noninvasive ventilation, or invasive ventilation including ECMO. The permuted block (four patients per block) randomization sequence, including stratification, was prepared by a statistician not involved in the trial, using SAS software, version 9.4 (SAS Institute). To minimize allocation bias, we performed allocation concealment with an interactive Web-based response system until randomization was finished on the system through a computer or phone.

The trial was approved by the institutional review board of Jin Yin-Tan Hospital. Written informed consent was obtained from all patients or from the patient’s legal representative if the patient was too unwell to provide consent. The trial was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonisation. The authors were responsible for designing the trial and for compiling and analyzing the data. The authors vouch for the completeness and accuracy of the data and for the adherence of the trial to the protocol.

CLINICAL AND LABORATORY MONITORING

Patients were assessed once daily by trained nurses using diary cards that captured data on a seven-category ordinal scale and on safety from day 0 to day 28, hospital discharge, or death. Safety was monitored by the Good Clinical Practice office from Jin Yin-tan Hospital. Other clinical data were recorded using the WHO-ISARIC (World Health Organization–International Severe Acute Respiratory and Emerging Infections Consortium) case record form Serial oropharyngeal swab samples were obtained on day 1 (before lopinavir–ritonavir was administered) and on days 5, 10, 14, 21, and 28 until discharge or death had occurred and were tested at Teddy Clinical Research Laboratory (Tigermed–DiAn Joint Venture), using quantitative real-time RT-PCR  RNA was extracted from clinical samples with the MagNA Pure 96 system, detected and quantified by Cobas z480 qPCR (Roche), with the use of LightMix Modular SARS-CoV-2 (COVID19) assays (TIB MOBIOL). These samples were obtained for all 199 patients who were still alive at every time point. Sampling did not stop when a swab at a given time point was negative. Baseline throat swabs were tested for detection of E gene, RdRp gene, and N gene, and samples on the subsequent visits were quantitatively and qualitatively detected for E gene. Clinical data were recorded on paper case record forms and then double-entered into an electronic database and validated by trial staff.

OUTCOME MEASURES

The primary end point was the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first. The end point of clinical improvement was used in our previous influenza study and was also recommended by the WHO R&D Blueprint expert group. Ordinal scales have been used as end points in clinical trials in patients hospitalized with severe influenza. The seven-category ordinal scale consisted of the following categories: 1, not hospitalized with resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6, hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and 7, death.

Other clinical outcomes included clinical status as assessed with the seven-category ordinal scale on days 7 and 14, mortality at day 28, the duration of mechanical ventilation, the duration of hospitalization in survivors, and the time (in days) from treatment initiation to death. Virologic measures included the proportions with viral RNA detection over time and viral RNA titer area-under-the-curve (AUC) measurements.

Safety outcomes included adverse events that occurred during treatment, serious adverse events, and premature discontinuation of treatment. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

STATISTICAL ANALYSIS

The trial was initiated in rapid response to the Covid-19 public health emergency, at which time there was very limited information about clinical outcomes in hospitalized patients with Covid-19. The original total sample size was set at 160, since it would provide the trial with 80% power to detect a difference, at a two-sided significance level of α=0.05, of 8 days in the median time to clinical improvement between the two groups, assuming that the median time in the standard-care group was 20 days and that 75% of the patients would reach clinical improvement. The planned enrollment of 160 patients in the trial occurred quickly, and the assessment at that point was that the trial was underpowered; thus, a decision was made to continue enrollment by investigators. Subsequently, when another agent (remdesivir) became available for clinical trials, we decided to suspend enrollment in this trial.

Primary efficacy analysis was on an intention-to-treat basis and included all the patients who had undergone randomization. The time to clinical improvement was assessed after all patients had reached day 28, with failure to reach clinical improvement or death before day 28 considered as right-censored at day 28 (right-censoring occurs when an event may have occurred after the last time a person was under observation, but the specific timing of the event is unknown). The time to clinical improvement was portrayed by Kaplan–Meier plot and compared with a log-rank test. Hazard ratios with 95% confidence intervals were calculated by means of the Cox proportional-hazards model. Five patients who had been assigned to the lopinavir–ritonavir group did not receive any doses (three of them died within 24 hours) but were included in the intention-to-treat analysis, since no reciprocal removals occurred in the standard-care group. A modified intention-to-treat analysis that excluded three early deaths was also performed. Post hoc analyses include subgroup analysis for National Early Warning Score 2 (NEWS2) of 5 or below or greater than 5 and those who underwent randomization up to 12 days or more than 12 days after the onset of illness.

Because the statistical analysis plan did not include a provision for correcting for multiplicity in tests for secondary or other outcomes, results are reported as point estimates and 95% confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity, so the intervals should not be used to infer definitive treatment effects for secondary outcomes. Safety analyses were based on the patients’ actual treatment exposure. Statistical analyses were conducted with SAS software, version 9.4 (SAS Institute).

Why is this medication prescribed?

The combination of lopinavir and ritonavir is used with other medications to treat human immunodeficiency virus (HIV) infection. Lopinavir and ritonavir are in a class of medications called protease inhibitors. They work by decreasing the amount of HIV in the blood. When lopinavir and ritonavir are taken together, ritonavir also helps to increase the amount of lopinavir in the body so that the medication will have a greater effect. Although lopinavir and ritonavir will not cure HIV, these medications may decrease your chance of developing acquired immunodeficiency syndrome (AIDS) and HIV-related illnesses such as serious infections or cancer. Taking these medications along with practicing safer sex and making other life-style changes may decrease the risk of transmitting the HIV virus to other people.

How should this medicine be used?

The combination of lopinavir and ritonavir comes as a tablet and a solution (liquid) to take by mouth. It is usually taken twice a day, but may be taken once a day by certain adults. The solution must be taken with food. The tablets may be taken with or without food. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take lopinavir and ritonavir exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them.

If you are using the solution, shake it well before each use to mix the medication evenly. Use a dose-measuring spoon or cup to measure the correct amount of liquid for each dose, not a regular household spoon.

Continue to take lopinavir and ritonavir even if you feel well. Do not stop taking lopinavir and ritonavir without talking to your doctor. If you miss doses, take less than the prescribed amount, or stop taking lopinavir and ritonavir, your condition may become more difficult to treat.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking lopinavir and ritonavir,

• tell your doctor and pharmacist if you are allergic to lopinavir, ritonavir (Norvir), any other medications, or any of the ingredients in lopinavir and ritonavir tablets or solution. Ask your pharmacist for a list of the ingredients.
• tell your doctor if you are taking any of the following medications: alfuzosin (Uroxatral); apalutamide (Erleada); cisapride (Propulsid) (not available in the U.S.); colchicine (Colcrys, Mitigare) in people with kidney or liver disease; dronedarone (Multaq); elbasvir and grazoprevir (Zepatier); ergot medications such as dihydroergotamine (D.H.E. 45, Migranal), ergotamine (Ergomar, in Cafergot, in Migergot), and methylergonovine (Methergine); lomitapide (Juxtapid); lovastatin (Altoprev); lurasidone (Latuda); midazolam taken by mouth (Versed); pimozide (Orap); ranolazine (Ranexa); rifampin (Rimactane, Rifadin, in Rifamate, in Rifater); sildenafil (only Revatio brand used for lung disease); simvastatin (Zocor, in Vytorin); St. John's wort; or triazolam (Halcion). Your doctor will probably tell you not to take lopinavir and ritonavir if you are taking one or more of these medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking. Be sure to mention any of the following: anticoagulants ('blood thinners') such as warfarin (Coumadin, Jantoven) and rivaroxaban (Xarelto); antifungals such as itraconazole (Onmel, Sporanox), isavuconazonium (Cresemba), ketoconazole (Nizoral), and voriconazole (Vfend); atovaquone (Mepron, in Malarone); bedaquiline (Sirturo); beta-blockers; bosentan (Tracleer); bupropion (Wellbutrin, Zyban, others); calcium-channel blockers such as felodipine, nicardipine (Cardene), and nifedipine (Adalat, Afeditab CR, Procardia); cholesterol-lowering medications such as atorvastatin (Lipitor, in Caduet), and rosuvastatin (Crestor); clarithromycin (Biaxin, in Prevpac); digoxin (Lanoxin); elagolix (Orilissa); fentanyl (Actiq, Duragesic, Onsolis, others); fosamprenavir (Lexiva); certain medications for cancer such as abemaciclib (Verzenio), dasatinib (Sprycel), encorafenib (Braftovi), ibrutinib (Imbruvica), ivosidenib (Tibsovo), neratinib (Nerlynx), nilotinib (Tasigna), venetoclax (Venclexta), vinblastine, and vincristine; certain medications for irregular heartbeat such as amiodarone (Cordarone, Nexterone, Pacerone), bepridil (no longer available in US; Vascor), lidocaine (Lidoderm; in Xylocaine with Epinephrine), and quinidine (in Nuedexta); certain medications for hepatitis C virus (HCV) such as boceprevir (Victrelis; no longer available in U.S.); glecaprevir and pibrentasvir (Mavyret); simeprevir (no longer available in U.S.; Olysio); sofosbuvir, velpatasvir, and voxilaprevir (Sovaldi, Epclusa, Vosevi); and paritaprevir, ritonavir, ombitasvir, and/or dasabuvir (Viekira Pak); certain medications for seizures such as carbamazepine (Equetro, Tegretol, Teril, others), lamotrigine (Lamictal), phenobarbital,phenytoin (Dilantin, Phenytek), and valproate; medications that suppress the immune system such as cyclosporine (Gengraf, Neoral, Sandimmune), sirolimus (Rapamune), and tacrolimus (Astagraf, Prograf); methadone (Dolophine, Methadose); oral or inhaled steroids such as betamethasone, budesonide (Pulmicort), ciclesonide (Alvesco, Omnaris), dexamethasone, fluticasone (Flonase, Flovent, in Advair), methylprednisolone (Medrol), mometasone (in Dulera). prednisone (Rayos), and triamcinolone; other antiviral medications such as abacavir (Ziagen, in Epzicom, in Trizivir, others); atazanavir (Reyataz, in Evotaz), delavirdine (Rescriptor), efavirenz (Sustiva, in Atripla), indinavir (Crixivan), maraviroc (Selzentry), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir, in Kaletra), tenofovir (Viread, in Atripla, in Truvada), tipranavir (Aptivus), saquinavir (Invirase), and zidovudine (Retrovir, in Combivir, in Trizivir); quetiapine (Seroquel); rifabutin (Mycobutin); salmeterol (Serevent, in Advair); sildenafil (Viagra); tadalafil (Adcirca, Cialis); trazodone; and vardenafil (Levitra). If you are taking the oral solution, also tell your doctor if you are taking disulfiram (Antabuse) or metronidazole (Flagyl, in Nuvessa, in Vandazole). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• if you are taking didanosine, take it 1 hour before or 2 hours after you take lopinavir and ritonavir solution with food. If you are taking lopinavir and ritonavir tablets, you may take them on an empty stomach at the same time as you take didanosine.
• tell your doctor if you have or have ever had a prolonged QT interval (a rare heart problem that may cause irregular heartbeat, fainting, or sudden death), an irregular heartbeat, a low level of potassium in your blood, hemophilia, high cholesterol or triglycerides (fat) in the blood, pancreatitis (swelling of the pancreas), or heart or liver disease.
• you should know that lopinavir and ritonavir may decrease the effectiveness of hormonal contraceptives (birth control pills, patches, rings, or injections). Talk to your doctor about using another form of birth control.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking lopinavir and ritonavir, call your doctor. You should not breast-feed if you are infected with HIV or if you are taking lopinavir and ritonavir.
• you should know that certain ingredients in lopinavir and ritonavir solution may cause serious and life-threatening side effects in newborn babies. Lopinavir and ritonavir oral solution should not be given to full-term babies younger than 14 days old or to premature babies younger than 14 days past their original due date, unless a doctor thinks there is a good reason for the baby to receive the medication right after birth. If your baby's doctor chooses to give your baby lopinavir and ritonavir solution immediately after birth, your baby will be monitored carefully for signs of serious side effects. Call your baby's doctor immediately if your baby is very sleepy or has changes in breathing during his or her treatment with lopinavir and ritonavir oral solution.
• you should be aware that your body fat may increase or move to different areas of your body, such as your upper back, neck (''buffalo hump''), breasts, and around your stomach. You may notice a loss of body fat from your face, legs, and arms.
• you should know that you may experience hyperglycemia (increases in your blood sugar) while you are taking this medication, even if you do not already have diabetes. Tell your doctor immediately if you have any of the following symptoms while you are taking lopinavir and ritonavir: extreme thirst, frequent urination, extreme hunger, blurred vision, or weakness. It is very important to call your doctor as soon as you have any of these symptoms, because high blood sugar that is not treated can cause a serious condition called ketoacidosis. Ketoacidosis may become life-threatening if it is not treated at an early stage. Symptoms of ketoacidosis include: dry mouth, nausea and vomiting, shortness of breath, breath that smells fruity, and decreased consciousness.
• you should know that while you are taking medications to treat HIV infection, your immune system may get stronger and begin to fight other infections that were already in your body. This may cause you to develop symptoms of those infections. If you have new or worsening symptoms after starting treatment with lopinavir and ritonavir, be sure to tell your doctor.

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

What side effects can this medication cause?

Lopinavir and ritonavir may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• weakness
• diarrhea
• gas
• heartburn
• weight loss
• headache
• difficulty falling asleep or staying asleep
• muscle pain
• numbness, burning, or tingling in the hands or feet
• stomach pain, nausea, and vomiting

Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately or get emergency medical treatment:

• nausea
• vomiting
• stomach pain
• extreme tiredness
• loss of appetite
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• itchy skin
• dizziness
• lightheadedness
• fainting
• irregular heartbeat
• blisters
• rash

Lopinavir and ritonavir may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA)

What should I know about storage and disposal of this medication?

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store the tablets at room temperature and protect them from excess moisture. It is best to keep the tablets in the container they came in; if you must take them out of the container, you should use them within 2 weeks. You may keep the oral solution in the refrigerator until the expiration date printed on the label, or you may store it at room temperature for up to 2 months.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach.Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines for more information if you do not have access to a take-back program.

In case of emergency/overdose

In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also If the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services at 911.

It is especially important to get medical help right away if a child drinks more than the usual dose of the solution. The solution contains a large amount of alcohol and other ingredients that could be very harmful to a child.

What other information should I know?

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to lopinavir and ritonavir.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.