COMPOSITION
Each ml contains:
Lopinavir 80mg
Ritonavir 20mg
Alcohol IP 42.4%v/v

PHARMACEUTICAL FORM
Oral Solution (Syrup)

CLINICAL PARTICULARS
Antiretroviral drugs

Therapeutic Indications
Lopinavir/Ritonavir oral solution is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infected adults, adolescents and children above the age of 2 years. The choice of Lopinavir/Ritonavir oral solution to treat protease inhibitor experienced HIV-1 infected patients should be based on individual viral resistance testing and treatment history of patients.

Method of administration
Adult and adolescent use: the recommended dosage of Lopinavir/Ritonavir oral solution is 5 ml of oral solution (400/100 mg) twice daily taken with food. Paediatric use (2 years of age and above): the recommended dosage of Lopinavir/Ritonavir oral solution is 230/57.5 mg/m2 twice daily taken with food, up to a maximum dose of 400/100 mg twice daily. The 230/57.5 mg/m2 dosage might be insufficient in some children when co-administered with nevirapine or efavirenz. An increase of the dose of Lopinavir/Ritonavir oral solution to 300/75 mg/m2 should be considered in these patients. Dose should be administered using a calibrated oral dosing syringe. The oral solution is the recommended option for the most accurate dosing in children based on body surface area.

Paediatric dosing guidelines for the dose 230/57.5 mg/m2

* Body surface area can be calculated with the following equation
BSA (m2) = √ (Height (cm) X Weight (kg) / 3600)

Children less than 2 years of age: the safety and efficacy of Lopinavir/Ritonavir oral solution in children aged less than 2 years have not yet been established. Total amounts of alcohol and propylene glycol from all medicines, including Lopinavir/Ritonavir oral solution, that are to be given to infants should be taken into account in order to avoid toxicity from these excipients.

Hepatic impairment: In HIV-infected patients with mild to moderate hepatic impairment, an increase of approximately 30% in lopinavir exposure has been observed but is not expected to be of clinical relevance. No data are available in patients with severe hepatic impairment. Lopinavir/Ritonavir oral solution must not be given to these patients.

Renal impairment: since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Contraindications
Hypersensitivity to the active substances or to any of the excipients.
Severe hepatic insufficiency.
Special warning and special precautions for use
Patients with coexisting conditions
Hepatic impairment: the safety and efficacy of Lopinavir & Ritonavir Oral Solution has not been established in patients with significant underlying liver disorders. Lopinavir & Ritonavir Oral Solution is contraindicated in patients with severe liver impairment. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

Renal impairment: since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Haemophilia: there have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia 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 if treatment had been discontinued.
Lipid elevations
Treatment with Lopinavir & Ritonavir Oral Solution has resulted in increases, sometimes marked, in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing is to be performed prior to initiating Lopinavir & Ritonavir Oral Solution therapy and at periodic intervals during therapy.
Pancreatitis
Cases of pancreatitis have been reported in patients receiving Lopinavir & Ritonavir Oral Solution, including those who developed hypertriglyceridaemia. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis.

Hyperglycaemia
New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been reported in patients receiving protease inhibitors. In some of these the hyperglycaemia was severe and in some cases also associated with ketoacidosis.
Fat redistribution & metabolic disorders
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated
metabolic disturbances.
Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART.

Interaction with other medicaments and other forms of interaction
Lopinavir & Ritonavir Oral Solution contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Lopinavir & Ritonavir Oral Solution is likely to increase plasma concentrations of medicinal products that are primarily metabolised by CYP3A. These increases of plasma concentrations of co-administered medicinal products could increase or prolong their therapeutic effect and adverse events.
Concomitant administration with colchicine, notably in patients with renal or hepatic impairment, should be avoided.The combination of Lopinavir & Ritonavir Oral Solution with:
- tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended
- fusidic acid in osteo-articular infections is not recommended
- salmeterol is not recommended.
- rivaroxaban is not recommended.

Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus.

Breastfeeding
Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal product is excreted in human milk. HIV-infected women must not breast-feed their infants under any circumstances to avoid transmission of
HIV.
Fertility
Animal studies have shown no effects on fertility. No human data on the effect of Lopinavir/Ritonavir on fertility are available.

Undesirable effects
The safety of Lopinavir & Ritonavir Oral Solution has been investigated in over 2600 patients in Phase II-IV clinical trials, of which over 700 have received a dose of 800/200 mg once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, Lopinavir & Ritonavir Oral Solution was used in combination with efavirenz or nevirapine.

The most common adverse reactions related to Lopinavir & Ritonavir Oral Solution therapy during clinical trials were diarrhoea, nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. The risk of diarrhoea may be greater with once daily dosing of Lopinavir & Ritonavir Oral Solution. Diarrhoea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolemia may occur later. Cushing's syndrome has been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide.

Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors. Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4). In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.

Overdose and Treatment
To date, there is limited human experience of acute overdose with Lopinavir & Ritonavir Oral Solution. Overdoses with Lopinavir & Ritonavir Oral Solution oral solution have been reported (including fatal outcome). The following events have been reported in association with unintended overdoses in preterm neonates: complete atrioventricular block, cardiomyopathy, lactic acidosis, and acute renal failure. The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/abnormal stool. The signs of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation, dehydration and tremors. There is no specific antidote for overdose with Lopinavir & Ritonavir Oral Solution.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic Properties
Mechanism of action: Lopinavir provides the antiviral activity of Lopinavir & Ritonavir Oral Solution. Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus.

Effects on the electrocardiogram: QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) and 13.1(15.8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively. The induced QRS interval prolongation from 6 ms to 9.5 ms with high dose Lopinavir/Ritonavir (800/200 mg twice daily) contributes to QT prolongation. The two regimens resulted in exposures on Day 3 which were approximately 1.5 and 3-fold higher than those observed with recommended once daily or twice daily LPV/r doses at steady state. No subject experienced an increase in QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Pharmacokinetic Properties
Absorption: multiple dosing with 400/100 mg Lopinavir & Ritonavir Oral Solution twice daily for 2 weeks and without meal restriction produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 12.3 ± 5.4 μ g/ml, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 8.1 ± 5.7 μ g/ml. Lopinavir AUC over a 12 hour dosing interval averaged 113.2 ± 60.5 μ g•h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established.

Effects of food on oral absorption: Lopinavir & Ritonavir Oral Solution soft capsules and liquid have been shown to be bioequivalent under nonfasting conditions (moderate fat meal). Administration of a single 400/100 mg dose of Lopinavir & Ritonavir Oral Solution soft capsules with a moderate fat meal (500 – 682 kcal, 22.7 –25.1% from fat) was associated with a mean increase of 48% and 23% in lopinavir AUC and Cmax, respectively, relative to fasting. For Lopinavir & Ritonavir Oral Solution oral solution, the corresponding increases in lopinavir AUC and Cmax were 80% and 54%, respectively.

Administration of Lopinavir & Ritonavir Oral Solution with a high fat meal (872 kcal, 55.8% from fat) increased lopinavir AUC and Cmax by 96% and 43%, respectively, for soft capsules, and 130% and 56%, respectively, for oral solution. To enhance bioavailability and minimise variability Lopinavir & Ritonavir Oral Solution is to be taken with food.

Distribution: at steady state, lopinavir is approximately 98 − 99% bound to serum 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 Lopinavir & Ritonavir Oral Solution twice daily, and is similar between healthy volunteers and HIV-positive patients. Biotransformation: in vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Lopinavir & Ritonavir Oral Solution dose was due to parent active substance. At least 13 lopinavir oxidative metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minute amounts of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.

Elimination: after a 400/100 mg 14C-Lopinavir/Ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and faeces, respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the administered dose in urine and faeces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged 5 − 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 l/h.

Paediatrics:
There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics of Lopinavir & Ritonavir Oral Solution 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in a total of 53 paediatric patients, ranging in age from 6 months to 12 years. The lopinavir mean steady-state AUC, Cmax, and Cmin were 72.6 ± 31.1 μ g•h/ml, 8.2 ± 2.9 μ g/ml and 3.4 ± 2.1 μ g/ml, respectively after Lopinavir & Ritonavir Oral Solution 230/57.5 mg/m2 twice daily without nevirapine (n=12), and were 85.8 ± 36.9 μ g•h/ml, 10.0 ± 3.3 μ g/ml and 3.6 ± 3.5 μ g/ml, respectively after 300/75 mg/m2 twice daily with nevirapine (n=12). The 230/57.5 mg/m2 twice daily regimen without
nevirapine and the 300/75 mg/m2 twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine. 31.1 μg•h/ml, 8.2 ± 2.9 μg/ml and 3.4 ± 2.1 μg/ml, respectively after Lopinavir & Ritonavir Oral Solution 230/57.5 mg/m2 twice daily without nevirapine (n=12), and were 85.8 ± 36.9 μg•h/ml, 10.0 ± 3.3 μg/ml and 3.6 ± 3.5 μg/ml, respectively after 300/75 mg/m2 twice daily with nevirapine (n=12). The 230/57.5 mg/m2 twice daily regimen without nevirapine and the 300/75 mg/m2 twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine. Gender, Race and Age: Lopinavir & Ritonavir Oral Solution pharmacokinetics have not been studied in the elderly. No age or gender related pharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due to race have not been identified.
Renal Insufficiency:
Lopinavir & Ritonavir Oral Solution pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.
Hepatic Insufficiency:
The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic function in a multiple dose study with Lopinavir/Ritonavir 400/100 mg twice daily. A limited increase in total lopinavir concentrations of approximately 30% has been observed which is not expected to be of clinical relevance (see section 4.2).

Shelf Life
18 months from the date of manufacturing.

Special Precautions for Storage
Store at 2°-8°C. Avoid exposure to excessive heat.
For patient use, refrigerated oral solution remains stable until the expiration date printed on the label. If stored at room
temperature up to 25°C oral solution should be used within 2 months.
Keep out of reach of children

Nature and Contents of container
60 ml, 100 ml, 240 ml &300 ml oral solution filled in PET bottles; labeled bottle are put in a carton along with a leaflet.
Instructions for user handling
Carefully read the instructions before use. Consult your doctor for further information.
“Use upon doctor’s prescription only”.