Lopinavir and Ritonavir interacts in the following cases:
Concentrations may be increased when co-administered with lopinavir/ritonavir.
Caution is warranted and therapeutic drug concentration monitoring is recommended when available.
It is not recommended to co-administer lopinavir/ritonavir and sofosbuvir/velpatasvir/voxilaprevir.
Serum concentrations of sofosbuvir, velpatasvir and voxilaprevir may be increased due to P-glycoprotein, BCRP and OATP1B1/3 inhibition by lopinavir/ritonavir. However, only the increase in voxilaprevir exposure is considered clinically relevant.
Concentrations may be reduced due to increased glucuronidation by lopinavir/ritonavir.
The clinical significance of reduced abacavir and zidovudine concentrations is unknown.
Afatinib:
AUC: ↑
Cmax: ↑
The extent of increase depends on the timing of ritonavir administration.
Due to BCRP (breast cancer resistance protein/ABCG2) and acute P-gp inhibition by lopinavir/ritonavir.
Caution should be exercised in administering afatinib with lopinavir/ritonavir. Refer to the afatinib SmPC for dosage adjustment recommendations. Monitor for ADRs related to afatinib.
Apalutamide is a moderate to strong CYP3A4 inducer and this may lead to a decreased exposure of lopinavir/ritonavir.
Serum concentrations of apalutamide may be increased due to CYP3A inhibition by lopinavir/ritonavir.
Decreased exposure of lopinavir/ritonavir may result in potential loss of virological response.
In addition, co-administration of apalutamide and lopinavir/ritonavir may lead to serious adverse events including seizure due to higher apalutamide levels. Concomitant use of lopinavir/ritonavir with apalutamide is not recommended.
A more pronounced effect on bedaquiline plasma exposures may be observed during prolonged co-administration with lopinavir/ritonavir.
CYP3A4 inhibition likely due to lopinavir/ritonavir.
Due to the risk of bedaquiline related adverse events, the combination of bedaquiline and lopinavir/ritonavir should be avoided. If the benefit outweighs the risk, co-administration of bedaquiline with lopinavir/ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended.
Lopinavir/ritonavir plasma concentrations may decrease due to CYP3A4 induction by bosentan.
Caution should be exercised in administering lopinavir/ritonavir with bosentan. When lopinavir/ritonavir is administered concomitantly with bosentan, the efficacy of the HIV therapy should be monitored and patients should be closely observed for bosentan toxicity, especially during the first week of co-administration.
Carbamazepine: Serum concentrations may be increased due to CYP3A inhibition by lopinavir/ritonavir.
Lopinavir: Concentrations may be decreased due to CYP3A induction by carbamazepine and phenobarbital.
Caution should be exercised in administering carbamazepine or phenobarbital with lopinavir/ritonavir. Carbamazepine and phenobarbital levels should be monitored when co-administering with lopinavir/ritonavir. When co-administered with carbamazepine or phenobarbital, an increase of lopinavir/ritonavir dosage may be envisaged. Dose adjustment has not been evaluated in clinical practice. Lopinavir/ritonavir must not be administered once daily in combination with carbamazepine and phenobarbital.
Concentrations may be increased due to CYP3A inhibition by lopinavir/ritonavir.
More frequent therapeutic concentration monitoring is recommended until plasma levels of these products have been stabilised.
Moderate increases in clarithromycin AUC are expected due to CYP3A inhibition by lopinavir/ritonavir.
For patients with renal impairment (CrCL <30 ml/min) dose reduction of clarithromycin should be considered. Caution should be exercised in administering clarithromycin with lopinavir/ritonavir to patients with impaired hepatic or renal function.
A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with lopinavir/ritonavir is required. Refer to colchicine prescribing information.
A more pronounced effect on DM-6705 (delamanid active metabolite) exposure may be observed during prolonged coadministration with lopinavir/ritonavir.
Due to the risk of QTc prolongation associated with DM-6705, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very frequent ECG monitoring throughout the full delamanid treatment period is recommended.
Plasma concentrations may be increased due to P-glycoprotein inhibition by lopinavir/ritonavir. The increased digoxin level may lessen over time as P-gp induction develops.
Caution is warranted and therapeutic drug monitoring of digoxin concentrations, if available, is recommended in case of co-administration of lopinavir/ritonavir and digoxin. Particular caution should be used when prescribing lopinavir/ritonavir in patients taking digoxin as the acute inhibitory effect of ritonavir on P-gp is expected to significantly increase digoxin levels. Initiation of digoxin in patients already taking lopinavir/ritonavir is likely to result in lower than expected increases of digoxin concentrations.
Lopinavir/ritonavir dosage should beincreased to 500/125 mg twice daily when co-administered with efavirenz. Lopinavir/ritonavir must not be administered once daily in combination with efavirenz.
Concentrations may be increased due to CYP3A inhibition by lopinavir/ritonavir.
Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with lopinavir/ritonavir.
Increased risk of side-effects (respiratory depression, sedation) due to higher plasma concentrations because of CYP3A4 inhibition by lopinavir/ritonavir.
Careful monitoring of adverse effects (notably respiratory depression but also sedation) is recommended when fentanyl is concomitantly administered with lopinavir/ritonavir.
Co-administration of increased doses of fosamprenavir (1400 mg BID) with lopinavir/ritonavir (533/133 mg BID) to protease inhibitor-experienced patients resulted in a higher incidence of gastrointestinal adverse events and elevations in triglycerides with the combination regimen without increases in virological efficacy, when compared with standard doses of fosamprenavir/ritonavir. Concomitant administration of these medicinal products is not recommended.
Lopinavir/ritonavir must not be administered once daily in combination with amprenavir.
Concentrations may be increased due to CYP3A inhibition by lopinavir/ritonavir.
When used for osteoarticular infections, where the coadministration is unavoidable, close clinical monitoring for muscular adverse events is strongly recommended.
Serum concentrations may be increased due to CYP3A inhibition by lopinavir/ritonavir.
High doses of ketoconazole and itraconazole (>200 mg/day) are not recommended.
Patients should be monitored closely for a decreased VPA effect when lopinavir/ritonavir and valproic acid or valproate are given concomitantly.
In patients starting or stopping lopinavir/ritonavir while currently taking maintenance dose of lamotrigine: lamotrigine dose may need to be increased if lopinavir/ritonavir is added, or decreased if lopinavir/ritonavir is discontinued; therefore plasma lamotrigine monitoring should be conducted, particularly before and during 2 weeks after starting or stopping lopinavir/ritonavir, in order to see if lamotrigine dose adjustment is needed.
In patients currently taking lopinavir/ritonavir and starting lamotrigine: no dose adjustments to the recommended dose escalation of lamotrigine should be necessary.
The dose of maraviroc should be decreased to 150 mg twice daily during co-administration with lopinavir/ritonavir 400/100 mg twice daily.
Lopinavir/ritonavir dosage should be increased to 500/125 mg twice daily when co-administered with nevirapine. Lopinavir/ritonavir must not be administered once daily in combination with nevirapine.
Phenytoin: Steady-state concentrations was moderately decreased due to CYP2C9 and CYP2C19 induction by lopinavir/ritonavir.
Lopinavir: Concentrations are decreased due to CYP3A induction by phenytoin.
Caution should be exercised in administering phenytoin with lopinavir/ritonavir. Phenytoin levels should be monitored when co-administering with lopinavir/ritonavir. When co-administered with phenytoin, an increase of lopinavir/ritonavir dosage may be envisaged. Dose adjustment has not been evaluated in clinical practice.
opinavir/ritonavir must not be administered once daily in combination with phenytoin.
When given with lopinavir/ritonavir the recommended dose of rifabutin is 150 mg 3 times per week on set days (for example Monday-Wednesday-Friday). Increased monitoring for rifabutin-associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to rifabutin. Further dosage reduction of rifabutin to 150 mg twice weekly on set days is recommended for patients in whom the 150 mg dose 3 times per week is not tolerated.
It should be kept in mind that the twice weekly dosage of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure. No dose adjustment is needed for lopinavir/ritonavir.
Large decreases in lopinavir concentrations may be observed due to CYP3A induction by rifampicin.
Co-administration of lopinavir/ritonavir with rifampicin is not recommended as the decrease in lopinavir concentrations may in turn significantly decrease the lopinavir therapeutic effect.
A dose adjustment of lopinavir/ritonavir 400 mg/400 mg (i.e. lopinavir/ritonavir 400/100 mg + ritonavir 300 mg) twice daily has allowed compensating for the CYP3A4 inducer effect of rifampicin. However, such a dose adjustment might be associated with ALT/AST elevations and with increase in gastrointestinal disorders. Therefore, this co-administration should be avoided unless judged strictly necessary.
If this co-administration is judged unavoidable, increased dose of lopinavir/ritonavir at 400 mg/400 mg twice daily may be administered with rifampicin under close safety and therapeutic drug monitoring. The lopinavir/ritonavir dose should be titrated upward only after rifampicin has been initiated.
Concomitant use of lopinavir/ritonavir with rilpivirine causes an increase in the plasma concentrations of rilpivirine, but no dose adjustment is required.
When co-administered with lopinavir/ritonavir, sildenafil doses must not exceed 25 mg in 48 hours.
For the treatment of pulmonary arterial hypertension:
Co-administration of lopinavir/ritonavir with tadalafil is not recommended.
For erectile dysfunction:
Particular caution must be used when prescribing sildenafil or tadalafil in patients receiving lopinavir/ritonavir with increased monitoring for adverse events including hypotension, syncope, visual changes and prolonged erection. Tadalafil doses must not exceed 10 mg every 72 hours.
No dose adjustment necessary. Higher tenofovir concentrations could potentiate tenofovir associated adverse events, including renal disorders.
Concomitant administration of these medicinal products is not recommended.
Adverse events of nausea, dizziness, hypotension and syncope were observed following co-administration of trazodone and ritonavir.
It is unknown whether the combination of lopinavir/ritonavir causes a similar increase in trazodone exposure. The combination should be used with caution and a lower dose of trazodone should be considered.
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.
Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 during the first trimester.
In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January 1989, an increased risk of birth defects exposures with lopinavir/ritonavir has not been reported among over 1000 women exposed during the first trimester. The prevalence of birth defects after any trimester exposure to lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defects suggestive of a common etiology was seen. Studies in animals have shown reproductive toxicity. Based on the data mentioned, the malformative risk is unlikely in humans. Lopinavir can be used during pregnancy if clinically needed.
Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal product is excreted in human milk. As a general rule, it is recommended that women living with HIV do not breast-feed their babies in order to avoid transmission of HIV.
Animal studies have shown no effects on fertility. No human data on the effect of lopinavir/ritonavir on fertility are available.
No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed that nausea has been reported during treatment with lopinavir/ritonavir.
The safety of lopinavir/ritonavir 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 was used in combination with efavirenz or nevirapine.
The most common adverse reactions related to lopinavir/ritonavir therapy during clinical trials were diarrhoea, nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. Diarrhoea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolemia may occur later. Treatment emergent adverse events led to premature study discontinuation for 7% of subjects from Phase II-IV studies.
It is important to note that cases of pancreatitis have been reported in patients receiving lopinavir/ritonavir, including those who developed hypertriglyceridaemia. Furthermore, rare increases in PR interval have been reported during lopinavir/ritonavir therapy.
The following events have been identified as adverse reactions. The frequency category includes all reported events of moderate to severe intensity, regardless of the individual causality assessment. The adverse reactions are displayed by system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) and not known (cannot be estimated from the available data).
Undesirable effects in clinical studies and post-marketing in adult patients:
| System organ class | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | Very common | Upper respiratory tract infection |
| Common | Lower respiratory tract infection, skin infections including cellulitis, folliculitis and furuncle | |
| Blood and lymphatic system disorders | Common | Anaemia, leucopenia, neutropenia, lymphadenopathy |
| Immune system disorders | Common | Hypersensitivity including urticaria and angioedema |
| Uncommon | Immune reconstitution inflammatory syndrome | |
| Endocrine disorders | Uncommon | Hypogonadism |
| Metabolism and nutrition disorders | Common | Blood glucose disorders including diabetes mellitus, hypertriglyceridaemia, hypercholesterolemia, weight decreased, decreased appetite |
| Uncommon | Weight increased, increased appetite | |
| Psychiatric disorders | Common | Anxiety |
| Uncommon | Abnormal dreams, libido decreased | |
| Nervous system disorders | Common | Headache (including migraine), neuropathy (including peripheral neuropathy), dizziness, insomnia |
| Uncommon | Cerebrovascular accident, convulsion, dysgeusia, ageusia, tremor\ | |
| Eye disorders | Uncommon | Visual impairment |
| Ear and labyrinth disorders | Uncommon | Tinnitus, vertigo |
| Cardiac disorders | Uncommon | Atherosclerosis such as myocardial infarction, atrioventricular block, tricuspid valve incompetence |
| Vascular disorders | Common | Hypertension |
| Uncommon | Deep vein thrombosis | |
| Gastrointestinal disorders | Very common | Diarrhoea, nausea |
| Common | Pancreatitis, vomiting, gastrooesophageal reflux disease, gastroenteritis and colitis, abdominal pain (upper and lower), abdominal distension, dyspepsia, haemorrhoids, flatulence | |
| Uncommon | Gastrointestinal haemorrhage including gastrointestinal ulcer, duodenitis, gastritis and rectal haemorrhage, stomatitis and oral ulcers, faecal incontinence, constipation, dry mouth | |
| Hepatobiliary disorders | Common | Hepatitis including AST, ALT and GGT increases |
| Uncommon | Jaundice, hepatic steatosis, hepatomegaly, cholangitis, hyperbilirubinemia | |
| Skin and subcutaneous tissue disorders | Common | Rash including maculopapular rash, dermatitis/rash including eczema and seborrheic dermatitis, night sweats, pruritus |
| Uncommon | Alopecia, capillaritis, vasculitis | |
| Rare | Steven-Johnson syndrome, erythema multiforme | |
| Musculoskeletal and connective tissue disorders | Common | Myalgia, musculoskeletal pain including arthralgia and back pain, muscle disorders such as weakness and spasms |
| Uncommon | Rhabdomyolysis, osteonecrosis | |
| Renal and urinary disorders | Uncommon | Creatinine clearance decreased, nephritis, haematuria |
| Not known | Nephrolithiasis | |
| Reproductive system and breast disorders | Common | Erectile dysfunction, menstrual disorders - amenorrhoea, menorrhagia |
| General disorders and administration site conditions | Common | Fatigue including asthenia |
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.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
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. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment.
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.
In children 14 days of age and older, the nature of the safety profile is similar to that seen in adults (see Table in section b).
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