Kaletra Solution 80 mg / 20mg Oral Solution

KALETRA is indicated in combination with other antiretroviral medicines for the treatment of HIV-infection.

Posology
KALETRA should be initiated by medical practitioners who are experienced in the treatment of HIV infection.
Adults
The recommended oral dose of KALETRA is as follows:
KALETRA 400/100 mg (5,0 mL) twice daily taken with food
KALETRA 800/200 mg (10,0 mL) once daily taken with food, in patients with less than three lopinavir-associated mutations. There are insufficient data to support the use of once daily administration of KALETRA for adult patients with three or more lopinavir-associated mutations. KALETRA should not be administered once daily in combination with carbamazepine, Phenobarbitone or phenytoin (see section 4,5).
Concomitant Therapy
Omeprazole and Ranitidine
KALETRA SOLUTION can be used in combination with acid reducing medicines (omeprazole and ranitidine) with no dose adjustment.
Efavirenz, Nevirapine, Amprenavir or Nelfinavir
A dose increase of KALETRA to 533/133 mg (6,5 mL) twice daily taken with food should be considered when used in combination with efavirenz or nevirapine, amprenavir or nelfinavir in treatment experienced patients where reduced susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). See section 4,5. KALETRA should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, amprenavir or nelfinavir.
Paediatric patients
Total amounts of alcohol and propylene glycol from all medicines, including KALETRA SOLUTION, that are to be given to infants should be taken into account in order to avoid toxicity from these excipients (see sections 2, 4,4 and 4,9). In children 6 months to 12 years of age, the recommended dosage of KALETRA SOLUTION is 12,0/3,0 mg/kg for those 7 to less than 15 kg and 10,0/2,5 mg/kg for those 15 to 40 kg (approximately equivalent to 230/57,5 mg/m2) twice daily taken with food, up to a maximum dose of 400/100 mg in children greater than 40 kg (5,0 mL) twice daily. KALETRA should not be administered once-daily in paediatric patients. It is preferred that the prescriber calculate the approximate milligram dose for each individual child less than or equal to 12 years old and determine the corresponding volume of solution. Alternatively, the following table contains dosing guidelines for KALETRA SOLUTION based on body weight.

KALETRA is contra-indicated in patients with known hypersensitivity to lopinavir, ritonavir or any excipients listed in section 6,1.
KALETRA should not be co-administered concurrently with medicines that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These medicines are listed in Table 4.

Antigout medicines
Life-threatening and fatal medicine interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir (see section 4,3 and 4,5).
Anti-mycobacterial
Standard dose KALETRA should not be co-administered with rifampin because large decreases in lopinavir concentrations may significantly decrease the therapeutic effect (see section 4,5). Co-administration of bedaquiline with strong CYP3A4 inhibitors may increase the systemic exposure of bedaquiline, which could potentially increase the risk of bedaquiline-related adverse reactions (see section 4,5). Bedaquiline must be used cautiously with KALETRA, only if the benefit of co-administration outweighs the risk. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended. Co-administration of delamanid with a strong inhibitor of CYP3A (KALETRA) may slightly increase exposure to delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration of delamanid with KALETRA is considered necessary, frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4,5).
Antipsychotics
Due to CYP3A inhibition by KALETRA, concentrations of quetiapine are expected to increase, which may lead to quetiapine-related toxicities (see section 4,5).

KALETRA is an inhibitor of CYP3A (cytochrome P450 3A) both in vitro and in vivo. Co-administration of KALETRA and medicines primarily metabolised by CYP3A (e.g. dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and PDE5 inhibitors) may result in increased plasma concentrations of the other medicines that could increase or prolong its therapeutic and adverse effects. Medicines that are extensively metabolised by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with KALETRA. Medicines that are contra-indicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in Table 4 under section 4,3. KALETRA is metabolised by CYP3A. Co-administration of KALETRA and medicines that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect. Although not noted with concurrent ketoconazole, co-administration of KALETRA and other medicines that inhibit CYP3A may increase KALETRA plasma concentrations. Based on known metabolic profiles, clinically significant medicine interactions are not expected between KALETRA and desipramine (CYP2D6 probe), fluvastatin, dapsone, trimethoprim/sulfamethoxazole, erythromycin or azithromycin. These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with lopinavir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information.

Pregnancy
The safety of KALETRA in pregnant women has not been established, as there are no adequate and well-controlled studies in pregnant women.
Human Data
Risk Summary
KALETRA has been evaluated in 3,366 women during pregnancy. Available human data suggest that lopinavir/ritonavir does not increase the risk of overall major birth defects compared to the background rate.
Antiretroviral Pregnancy Registry
In post-marketing surveillance through the Antiretroviral Pregnancy Registry (APR), established since January 1989, no increased risk of birth defects has been reported among over 1000 women exposed to KALETRA in the first trimester.
Breastfeeding
HIV-infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving KALETRA. It is not known whether lopinavir is secreted in human milk.

No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed that nausea and dizziness has been reported during treatment with KALETRA (see section 4,8). Kaletra oral solution contains approximately 42 % v/v alcohol.

a. Summary of the safety profile
Not applicable
b. Tabulated summary of adverse reactions
Adults
Treatment-Emergent Adverse Events
The safety of KALETRA has been investigated in over 2,600 patients in Phase II-IV clinical trials, of which more than 700 have received a dose of 800/200 mg (4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, KALETRA was used in combination with efavirenz or nevirapine. Commonly reported adverse reactions to KALETRA included diarrhoea, nausea, vomiting, hypertriglyceridaemia and hypercholesterolaemia. Diarrhoea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolaemia may occur later. The following adverse reactions of moderate to severe intensity with possible or probable relationship to KALETRA have been reported. The adverse reactions are displayed by system organ class. Within the system organ class adverse reactions are listed by frequency, using the following groupings: very common >1/10; common >1/100, 1/1,000, <1/100.

Side effects can be exacerbated and exaggerated with overdose. The following events have been reported in association with unintended overdoses in pre-term neonates: complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure. KALETRA SOLUTION contains 42,4 % alcohol (v/v) and 15,3 % propylene glycol (w/v) which would result into significant alcohol toxicity in young children after overdose (see section 2; 4,2 and 4,4). Treatment of overdose with KALETRA should consists of symptomatic and supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with KALETRA. Administration of activated charcoal may also be used to aid in removal of unabsorbed medicine. Since KALETRA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the medicine. However, dialysis can remove both alcohol and propylene glycol in the case of overdose with KALETRA SOLUTION.