RITNA

Ritonavir should be administered by doctors experienced in the management of HIV infection.

When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors, the Summary of Product Characteristics of the other protease inhibitor should be consulted.

The following

HIV-1 protease inhibitors have been approved for use with ritonavir as a pharmacokinetic enhancer at the doses listed below.

Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily.

Atazanavir 300 mg once daily with ritonavir 100 mg once daily.

Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily.

Lopinavir combined with ritonavir (lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200 mg. Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in patients pre-treated with antiretrovirals (ARVs).

In ARV-naïve patients, initiate treatment with saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days, then saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily.

Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily.

Tipranavir with ritonavir should not be used in treatment-naïve patients.

Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in patients pre-treated with ARVs.

Darunavir 800 mg once daily with ritonavir 100 mg once daily may be used in some patients pre-treated with ARVs.

Characteristics for darunavir for more information on once-daily use in patients pre-treated with ARVs.

Darunavir 800 mg once daily with ritonavir 100 mg once daily in ARV-naïve patients.

Ritonavir is recommended for children aged 2 years and over.

For additional dosing recommendations, refer to the Summary of Product Characteristics for other protease inhibitors approved for co-administration with ritonavir.

As ritonavir is metabolized primarily by the liver, it should be used with caution as a pharmacokinetic enhancer in patients with renal impairment, depending on the protease inhibitor with which it is co-administered.

However, as renal clearance of ritonavir is negligible, a reduction in total body clearance in patients with renal impairment is unlikely.

For specific dosage information in patients with renal impairment, refer to the Summary of Product Characteristics (SmPC) of the co-administered protease inhibitor.

Ritonavir should not be administered as a pharmacokinetic enhancer in patients with decompensated liver disease.

In the absence of pharmacokinetic studies in patients with stable severe hepatic impairment (Child-Pugh class C) without decompensation, caution is recommended when ritonavir is used as a pharmacokinetic enhancer, due to the possible increase in concentrations of the co-administered PI.

Specific recommendations for the use of ritonavir as a pharmacokinetic enhancer in patients with hepatic impairment depend on the protease inhibitor with which it is co-administered.

Refer to the SPC of the co-administered PI for specific dosing information in this patient population.

The recommended dose of RITONAVIR

ARROW 100 mg, film-coated tablet is 600 mg (6 tablets) twice a day (i.e. 1,200 mg per day) Oral.

A gradual increase in the dose of ritonavir during the initial phase of treatment may help improve tolerability.

Treatment should be initiated at 300 mg (3 tablets) twice daily for three days and increased in doses of 100 mg (1 tablet) twice daily up to 600 mg twice daily over a period not exceeding 14 days.

Patients should not stay on the 300 mg twice daily dose for more than 3 days.

The recommended dosage of RITONAVIR

ARROW 100 mg, film-coated tablet is 350 mg/m 2 Oral twice daily and should not exceed 600 mg twice daily.

The dose of RITONAVIR

ARROW 100 mg, film-coated tablet should initially be 2

Patients receiving ritonavir or other antiretroviral therapy may still develop opportunistic infections and other complications of HIV-1 infection.

When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors, it is necessary to take into account the special warnings and special precautions of the co-administered PI and therefore consult the Summary of Product Characteristics of the concerned PI.

Ritonavir administered as an antiretroviral agent or pharmacokinetic enhancer Increased monitoring is recommended in the event of diarrhea.

The relatively high frequency of diarrhea occurring during treatment with ritonavir may compromise the absorption and effectiveness of ritonavir or other associated medicinal products (due to reduced patient compliance with treatment).

Serious and persistent vomiting and/or diarrhea associated with the use of ritonavir could have an impact on renal function.

It is advisable to monitor renal function in patients with renal insufficiency.

Cases of increased bleeding including spontaneous skin hematomas and hemarthroses have been reported in hemophilia type A and B patients treated with protease inhibitors.

Extra factor

VIII was given in some patients.

In more than half of the reported cases, it was possible to continue treatment with protease inhibitors or to resume it if it had been interrupted.

A causal relationship has been suggested, although the mechanism of action has not been elucidated.

Patients with hemophilia should therefore be informed of the possibility of increased bleeding.

An increase in body weight and blood lipid and glucose levels may occur during antiretroviral treatment.

Such changes may in part be related to disease control and lifestyle.

If for increases in lipid levels, it is well established in certain cases that there is an effect of treatment, no link is clearly established between weight gain and any antiretroviral treatment.

Control of blood lipid and glucose levels should take into account current recommendations for HIV treatments.

Lipid disorders should be managed according to the clinical picture.

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or laboratory abnormalities (such as increased serum amylase or lipase) suggestive of pancreatitis occur.

A patient who experiences these signs or symptoms should be evaluated and treatment with ritonavir discontinued if the diagnosis of pancreatitis is made.

In HIV-infected patients with severe immunodeficiency at the time of initiation of combination antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections may occur and lead to serious clinical manifestations or worsening of symptoms.

Such reactions were typically observed during the first weeks or months following initiation of combination antiretroviral treatment.

Relevant examples are cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jiroveci pneumonia.

Any inflammatory symptoms should be assessed and treatment initiated if necessary.

Autoimmune diseases (such as Graves'disease and autoimmune hepatitis) have also been reported in the context of immune reconstitution; however, the time to onset is more variable and clinical manifestations can occur many months after initiation of treatment.

Ritonavir should not be administered to patients with decompensated liver disease.

Patients with chronic hepatitis B or

C treated with a combination of antiretrovirals are at increased risk of serious and potentially fatal hepatic adverse effects.

In the event of concomitant antiviral treatment for hepatitis B or C, refer to the SmPC of the medicines concerned.

Patients with pre-existing hepatic dysfunction including chronic active hepatitis have an increased frequency of abnormal liver function.

Ritonavir administered as a pharmacokinetic enhancer or antiretroviral agent Ritonavir has a high affinity for several isoforms of cytochrome P450 (CYP), in the following descending order: CYP3A4 > CYP2D6.

Co-administration of ritonavir with a drug metabolized primarily by CYP3A may increase plasma concentrations of the co-administered drug, which may increase or prolong its therapeutic effect and adverse effects.

For some drugs (e.g. alprazolam), the inhibitory effects of ritonavir on CYP3A4 may diminish over time.

Ritonavir also has a high affinity for P-glycoprotein and can inhibit this transporter.

The inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may diminish over time (e.g. digoxin and fexofenadine – see the table “Effects of ritonavir on medicinal products other than concomitantly administered antiretrovirals” below).

Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 and thereby potentiate the metabolism of certain drugs metabolized by these pathways, which may lead to a decrease in systemic exposure to these drugs and reduce or shorten their therapeutic effect.

Important information regarding drug interactions when ritonavir is used as a pharmacokinetic enhancer is also included in the Summary of Product Characteristics of the co-administered protease inhibitor.

Serum concentrations of ritonavir may be decreased by concomitant use of herbal preparations containing St.

John's Wort (Hypericum perforatum).

This is due to

John's wort's induction of drug-metabolizing enzymes.

Therefore, herbal preparations containing St.

John's Wort should not be combined with ritonavir.

If a patient is already taking

John's Wort, taking St.

John's Wort should be stopped and, if possible, the viral load should be checked.

Ritonavir concentrations may increase when

John's Wort is stopped.

The dose of ritonavir may need adjustment.

The inducing effect may persist for at least two weeks after stopping treatment with St.

Serum concentrations of ritonavir may be altered when co-administered with certain drugs (e.g. delavirdine, efavirenz, phenytoin and rifampicin).

These interactions are described in the drug interaction tables below.

Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors, and drugs other than antiretrovirals are listed in the tables below.

This list is not exhaustive or complete.

SPC of each product must be consulted.

Drug interactions – Ritonavir and protease inhibitors Co-administered drug Dose of co-administered drug (mg) Dose of ritonavir (mg) Drug evaluated AUC C min Amprenavir 600 /12 hrs 100 /12 hrs Amprenavir 1 ↑ 64% x 5 Ritonavir increases serum concentrations of amprenavir by inhibition of CYP3A4.

Clinical studies have confirmed the safety and effectiveness of the combination of amprenavir 600 mg twice daily and ritonavir 100 mg twice daily.

For further information, physicians should refer to the amprenavir Summary of Product Characteristics.

Atazanavir 300 /24 h 100 /24 h Atazanavir ↑ 86% ↑ x 11 Atazanavir 2 ↑ x 2 ↑ x 3-7 Ritonavir increases serum concentrations of atazanavir by inhibition of CYP3A4.

Clinical studies have confirmed the safety and effectiveness of the combination of atazanavir 300 mg once daily and ritonavir 100 mg once daily in antiretroviral treatment-naïve patients.

For further information, physicians should refer to the Summary of Product Characteristics for atazanavir.

Darunavir 600, single 100 / 12 h Darunavir ↑ x 14 Ritonavir increases serum concentrations of darunavir by inhibition of CYP3A.

Darunavir must be administered with ritonavir to ensure its therapeutic effect.

Doses of ritonavir greater than 100 mg twice daily have not been studied with darunavir.

For further information, physicians should refer to the darunavir Summary of Product Characteristics.

Fosamprenavir 700 /12 h 100 /12 h Amprenavir ↑ x 2.4 ↑ x 11 Ritonavir increases serum concentrations of amprenavir (from fosamprenavir) by inhibition of CY This medicine does not require any special storage precautions.

mg, film-coated tablet is indicated in combination with other antiretrovirals for the treatment of patients infected with HIV-1 (adults and children 2 years and older).

Lopinavir and ritonavir tablets are a fixed-dose combination of HIV-1 antiviral drugs lopinavir and ritonavir.

As co-formulated in lopinavir and ritonavir tablets, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of lopinavir and ritonavir on QTcF interval was evaluated in a placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults.

The maximum mean timematched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 and 15.2 mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily lopinavir and ritonavir, respectively.

Lopinavir and ritonavir 800/200 mg twice daily resulted in a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax observed with the approved once daily and twice daily lopinavir and ritonavir doses at steady state.

The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 and 31.9 msec for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily lopinavir and ritonavir, respectively. 12.3 Pharmacokinetics The pharmacokinetic properties of lopinavir are summarized in Table 13.

The steady-state pharmacokinetic parameters of lopinavir are summarized in Table 14.

Under fed conditions, lopinavir concentrations were similar following administration of lopinavir and ritonavir tablets to capsules with less pharmacokinetic variability.Under fed conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of lopinavir and ritonavir capsules and oral solution.

Table 13.

Pharmacokinetic Properties of Lopinavir Absorption

Tmax (hr)a 4.4 ± 0.8 Effect of meal (relative to fasting) Tablet Oral Solution ↑ 19%b Distribution % Bound to human plasma proteins > 98 Vd/Fa (L) 16.9 Metabolism Metabolism CYP3A Elimination Major route of elimination hepatic t1/2 (h)a 6.9 ± 2.2 % of dose excreted in urine 10.4 ± 2.3 % of dose excreted in feces 82.6 ± 2.5 a.Lopinavir and ritonavir tablet b.

Changes in AUC values

Table 14.

Steady-State Pharmacokinetic Parameters of

Lopinavir, Mean ± SD Pharmacokinetic Parameter Twice Daily a Once Daily b Cmax (µg/mL) 9.8 ± 3.7 11.8 ± 3.7 Cmin (µg/mL) 5.5 ± 2.7 1.7 ± 1.6 AUCtau (µg•h/mL) 92.6 ± 36.7 154.1 ± 61.4 a.

HIV-1 subjects, Lopinavir and ritonavir 400/100 mg twice daily b.

HIV-1 subjects, Lopinavir and ritonavir 800/200 mg + emtricitabine 200 mg + tenofovir DF 300 mg Specific Populations Gender, Race and Age No gender or race related pharmacokinetic differences have been observed in adult patients.

Lopinavir pharmacokinetics have not been studied in elderly patients.

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.

Table 15.

Lopinavir Pharmacokinetic Data from Pediatric Clinical

Trials, Mean ± SD Cmax (μg/mL) Cmin (μg/mL) AUC12 (μg•hr/m ) Age ≥ 14 Days to < 6 Weeks Cohort (N = 9): 5.17 ± 1.84a 1.40 ± 0.48a 43.39 ± 14.80a Age ≥ 6 Weeks to < 6 Months Cohort (N = 18): 9.39 ± 4.91a 1.95 ± 1.80a 74.50 ± 37.87a Age ≥ 6 Months to ≤ 12 years Cohort (N = 24): 8.2 ± 2.9b 3.4 ± 2.1b 72.6 ± 31.1b 10.0 ± 3.3c 3.6 ± 3.5c 85.8 ± 36.9c Lopinavir and ritonavir oral solution300/75 mg/m2 twice daily without concomitant NNRTI therapy Lopinavir and ritonavir oral solution 230/57.5 mg/m2 twice daily without nevirapine (n=12) Lopinavir and ritonavir oral solution 300/75 mg/m2 twice daily with nevirapine (n=12) Pregnancy The C12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum in 12 HIV-infected pregnant women received lopinavir and ritonavir 400 mg/100 mg twice daily.

Yet this decrease is not considered clinically relevant in patients with no documented lopinavir and ritonavir -associated resistance substitutions receiving 400 mg/100 mg twice daily.

Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Multiple dosing of lopinavir and ritonavir 400/100 mg twice daily to HIV-1 and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-1 infected subjects with normal hepatic function (n = 12).

Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively).

Lopinavir and ritonavir has not been studied in patients with severe hepatic impairment.

Drug Interactions Lopinavir and ritonavir is an inhibitor of the P450 isoform CYP3A in vitro.

Lopinavir and ritonavir does not inhibit

CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.

Lopinavir and ritonavir has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.

The effects of co-administration of lopinavir and ritonavir on the AUC, Cmax and Cmin are summarized in Table 16 (effect of other drugs on lopinavir) and Table 17 (effect of lopinavir and ritonavir on other drugs).

For information regarding clinical recommendations, see Table in Drug Interactions.

Table 16.

Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug for Recommended Alterations in Dose or Regimen Co.

• administered Drug Dose of Co.

• administered Drug (mg) Dose of Lopinavir and Ritonavir (mg) n Ratio (in combination with Co-administered drug/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Cmax AUC Cmin Efavirenz1 600 at bedtime 400/100 capsule twice daily 11, 73 0.97 0.81 0.61 600 at bedtime 500/125 tablet twice daily 19 1.12 1.06 0.90 600 at bedtime 600/150 tablet twice daily 23 1.36 1.36 1.32 Etravirine 200 twice daily 400/100 mg twice day (tablets) 16 0.89 0.87 0.80 Fosamprenavir2 700 twice daily plus ritonavir 100 twice daily 400/100 capsule twice daily 18 1.30 1.37 1.52 Ketoconazole 200 single dose 400/100 capsule twice daily 12 0.89 0.87 0.75 Nelfinavir 1000 twice daily 400/100 capsule twice daily 13 0.79 0.73 0.62 Nevirapine 200 twice daily steady-state 400/100 capsule twice daily 22, 193 0.81 0.73 0.49 7 mg/kg or 4 mg/kg once daily; twice daily 1 wk5 (> 1 yr) 300/ 75 mg/m2 oral solution twice daily 12, 153 0.86 0.78 0.45 Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir2 25/150/100 + dasabuvir 400 400/100 tablet twice daily 6 0.87 0.94 1.15 Omeprazole 40 once daily, 5 d 400/100 tablet twice daily, 10 d 12 1.08 1.07 1.03 40 once daily, 5 d 800/200 tablet once daily, 10 d 12 0.94 0.92 0.71 Pravastatin 20 once daily, 4 d 400/100 capsule twice daily, 14 d 12 0.98 0.95 0.88 Ranitidine 150 single dose 400/100 tablet twice daily, 10 d 12 0.99 0.97 0.90 150 single dose 800/200 tablet once daily, 10 d 10 0.97 0.95 0.82 Rifabutin 150 once daily 400/100 capsule twice daily 14 1.08 1.17 1.20 Rifampin 600 once daily 400/100 capsule twice daily 22 0.45 0.25 0.01 600 once daily 800/200 capsule twice daily 10 1.02 0.84 0.43 600 once daily 400/400 capsule twice daily 9 0.93 0.98 1.03 Rilpivirine 150 once daily 400/100 twice daily (capsules) 15 0.96 0.99 0.89 Ritonavir 100 twice daily 400/100 capsule twice daily 8, 213 1.28 1.46 2.16 Tipranavir/ ritonavir 500/200 twice daily 400/100 capsule twice daily 21 693 0.53 0.45 0.30 0.484 1 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz.

Data extracted from the

U.S. prescribing information of co-administered drugs.

Parallel group design 4 Drug levels obtained at 8-16 hours post dose N/A = Not available.

Table 17.

Pharmacokinetic Parameters for Co-administered Drug in the Presence of Lopinavir And Ritonavir for Recommended Alterations in Dose or Regimen Co.

• administered Drug (mg) Dose of Lopinavir and Ritonavir (mg) n Ratio (in combination with Lpinavir and Ritonavir /alone) of Co.

• administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Cmax AUC Cmin Bedaquiline1 400 single dose 400/100 twice daily N/A N/A 1.22 N/A Efavirenz at bedtime 400/100 capsule twice daily 11, 123 0.91 0.84 0.84 Elbasvir/ grazoprevir1 50 once daily 400/100 twice daily 10 2.87 3.71 4.58 200 once daily 13 7.31 12.86 21.70 Ethinyl Estradiol 35 µg once daily (Ortho Novum®) 400/100 capsule twice daily 12 0.59 0.58 0.42 Etravirine 200 twice daily 400/100 tablet twice day 16 0.70 0.65 0.55 Fosamprenavir1 700 twice daily plus ritonavir 100 twice daily 400/100 capsule twice daily 18 0.42 0.37 0.35 Indinavir 600 twice daily combo nonfasting vs. 800 three times daily alone fasting 400/100 capsule twice daily 13 0.71 0.91 3.47 Ketoconazole 200 single dose 400/100 capsule twice daily 12 1.13 3.04 N/A Maraviroc1 300 twice daily 400/100 twice daily 11 1.97 3.95 9.24 Methadone 5 single dose 400/100 capsule twice daily 11 0.55 0.47 N/A Nelfinavir 1000 twice daily combo vs. 1250 twice daily alone 400/100 capsule twice daily 13 0.93 1.07 1.86 M8 metabolite 2.36 3.46 7.49 Nevirapine 200 once daily twice daily 400/100 capsule twice daily 5, 63 1.05 1.08 1.15 Norethindrone 1 once daily (Ortho Novum®) 400/100 capsule twice daily 12 0.84 0.83 0.68 Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir1 25/150/100 + dasabuvir 400 400/100 tablet twice daily 6 1.14 1.17 1.24 2.04 2.17 2.36 1.55 2.05 5.25 0.99 0.93 0.68 Pitavastatin1 4 once daily 400/100 tablet twice daily 23 0.96 0.80 N/A Pravastatin 20 once daily 400/100 capsule twice daily 12 1.26 1.33 N/A Rifabutin 150 once daily combo v.

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE03.

Pharmacokinetic potentiation by ritonavir is based on its action as a potent inhibitor of CYP3A-mediated metabolism.

The degree of potentiation is related to the metabolism of the co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the metabolism of ritonavir.

Maximal inhibition of metabolism of co-administered protease inhibitors is generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily and is dependent on the co-administered protease inhibitor.

For more information on the effects of ritonavir on the metabolism of co-administered protease inhibitors Ritonavir is an Oral active peptidomimetic inhibitor of HIV-1 and HIV-2 aspartyl proteases.

Inhibition of

HIV proteases renders the enzyme unable to synthesize the polyprotein precursor gag-pol, resulting in the production of HIV particles that are morphologically immature and incapable of initiating new infectious cycles.

Ritonavir has a selective affinity for

HIV protease and its inhibitory activity against human aspartyl proteases is very low.

Ritonavir (authorized in 1996) was the first protease inhibitor whose effectiveness was proven during a study with clinical endpoints.

However, due to its metabolism-inhibiting properties, ritonavir is mainly used in clinical practice as a pharmacokinetic potentiator of other protease inhibitors.

QTcF interval was evaluated in a randomized placebo.

• and active-controlled crossover study (moxifloxacin 400 mg once daily) in 45 healthy adult subjects, in which 10 measurements were taken over a 12-hour period on day 3.

The maximum difference in means in

QTcF from placebo was 5.5 for ritonavir 400 mg twice daily.

On day 3, ritonavir exposure was approximately 1.5 times higher than that observed at steady state with the dose of 600 mg twice daily.

No subject experienced a prolongation of

QTcF greater than or equal to 60 ms compared to initial values ​​nor a QTcF interval exceeding the possibly clinically significant threshold of 500 ms.

A slight prolongation of the

PR interval was also observed on day in subjects receiving ritonavir in the same study.

Mean changes in

PR interval from baseline ranged from 11.0-24.0 ms in the 12 hours post-dose.

The maximum

PR interval was 252 ms and no subject experienced 2nd or 3rd degree heart block.

Strains of

HIV-1 resistant to ritonavir were selected in vitro and isolated from patients treated with ritonavir at therapeutic doses.

The reduction in the antiretroviral activity of ritonavir is mainly associated with mutations in the V82A/F/T/S and I84V proteases.

The accumulation of other mutations in the protease gene (including mutations at positions and 90) may also contribute to resistance to ritonavir.

In general, when mutations associated with ritonavir resistance accumulate, sensitivity to other PIs may decrease due to cross-resistance.

Characteristics of other protease inhibitors or updated official recommendations should be consulted for specific information regarding protease mutations associated with decreased sensitivity to these compounds.

The effects of ritonavir (alone or in combination with other antiretroviral agents) on biological markers of viral activity such as CD4 cell counts and viral RNA have been investigated in several studies in HIV-1-infected patients.

The following studies are the most important.

A controlled study of ritonavir carried out in in patients infected with HIV-1, already treated with nucleoside analogues and whose CD4 cell count was less than or equal to 100 cells/µl showed a reduction in mortality and events indicative of AIDS.

The average decrease in viral

RNA after 16 weeks was -0.79 log10 (maximum average decrease.

Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer depend on the specific protease inhibitors co-administered.

Refer to the

SmPC information on co-administered specific protease inhibitors for information on adverse reactions.

Adverse reactions reported in adults during clinical trials and post-marketing The most commonly reported adverse reactions in patients receiving ritonavir alone or in combination with other antiretroviral medicines are gastrointestinal effects (including diarrhea, nausea, vomiting, abdominal pain ), neurological disorders (including paresthesia and oral paresthesia), and fatigue/asthenia.

The following adverse reactions of moderate to severe intensity, with possible or probable attributability to ritonavir, have been reported.

Within each frequency group, adverse reactions are presented in decreasing order of seriousness: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), frequency not known (cannot be determined from the available data).

Adverse reactions of unknown frequency have been identified post-marketing.

Adverse reactions reported in adults during clinical trials and post-marketing System organ class Frequency Adverse reactions Blood and lymphatic system disorders Common Decreased leukocyte count, decreased hemoglobin count, decreased neutrophil count, increased eosinophil count, thrombocytopenia Uncommon Increased neutrophil count Immune system disorders Common Hypersensitivity including urticaria and facial edema Rare Anaphylaxis Metabolism and nutritional disorders Common Hypercholesterolemia, hypertriglyceridemia, gout, peripheral edema and edema, dehydration (usually associated with gastrointestinal symptoms) Uncommon Diabetes mellitus Rare Hyperglycemia Nervous system disorders Very common Dysgeusia, oral and peripheral paresthesias, headache, dizziness, peripheral neuropathy Common Insomnia, anxiety, confusion, disturbances in attention, syncope, convulsions Eye disorders Common Blurred vision Cardiac disorders Uncommon Myocardial infarction Vascular disorders Common Hypertension, hypotension including orthostatic hypotension, coldness of the extremities Respiratory, thoracic and mediastinal disorders Very common Pharyngitis, oropharyngeal pain, cough Gastrointestinal disorders Very common Abdominal pain (high and low), nausea, diarrhea (including severe diarrhea with electrolyte imbalance), vomiting, dyspepsia Common Anorexia, flatulence, oral ulceration, gastrointestinal bleeding, gastroesophageal reflux, pancreatitis Hepatobiliary disorders Common Hepatitis (including increased ALT, AST, gGT), hyperbilirubinemia (including jaundice) Diseases skin and subcutaneous tissue Very common Pruritus, rash (including erythematous rash and maculopapular rash) Common Acne Rare Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) Musculoskeletal and systemic disorders Very common Arthralgia and back pain Common Myositis, rhabdomyolysis, myalgia, myopathy/increased CPK Renal and urinary tract disorders Common Pollakiuria, impaired renal function (e.g. oliguria, increased creatinine) Uncommon Acute renal failure Not known Nephrolithiasis Reproductive system and breast disorders Common Menorrhagia General disorders and administration site conditions Very common Fatigue including asthenia, flushing, feeling hot Common Fever, weight loss.

Investigations Common Increased blood pressure amylase, decreased levels of free and total thyroxine (T4) Uncommon Hyperglycemia, increased levels of magnesium, alkaline phosphatase An increase in transaminases to more than five times the upper limit of normal, hepatitis and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretroviral drugs.

An increase in body weight and blood lipid and glucose levels may occur during antiretroviral treatment.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

When ritonavir is used as a pharmacokinetic enhancer of other protease inhibitors (PIs), refer to the Summary of Product Characteristics of the co-administered protease inhibitor for information on contraindications.

Ritonavir should not be administered to patients with decompensated liver disease, whether used as an antiretroviral agent or a pharmacokinetic enhancer.

In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of biotransformations mediated by cytochrome P450 isoforms CYP3A and CYP2D6.

The drugs below are contraindicated with ritonavir and, unless otherwise noted, the contraindication is due to the potential of ritonavir to inhibit the metabolism of the co-administered drug, resulting in increased exposure to the drug and risk of clinically significant adverse reactions.

The enzyme modulatory effect of ritonavir may be dose dependent.

For some medicinal products, contraindications may be more relevant when ritonavir is used as an antiretroviral agent than as a pharmacokinetic enhancer (e.g. rifabutin and voriconazole).

Pharmacological class Medicinal products in the class Reason Increased or decreased concentrations of the co-administered medicinal product α1-adrenoceptor antagonist Alfuzosin Increased plasma concentrations of alfuzosin which may lead to severe hypotension.

Pethidine, propoxyphene Increased plasma concentrations of norpethidine and propoxyphene and, therefore, increased risk of serious respiratory depression or hematological abnormalities, or other serious adverse reactions due to these products.

Increased plasma concentrations of ranolazine which may increase the risk of serious and/or life-threatening adverse reactions.

Increased plasma concentrations of neratinib which may increase the risk of serious and/or life-threatening adverse reactions including hepatotoxicity.

Increased plasma concentrations of venetoclax.

Increased risk of tumor lysis syndrome at the initiation of treatment and during the dose titration phase.

Amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine Increased plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine and, therefore, increased risk of arrhythmias or other serious adverse reactions due to these products.

Antibiotic Fusidic acid

Increased plasma concentrations of fusidic acid and ritonavir.

Concomitant use of ritonavir (400 mg twice daily and above) and voriconazole is contraindicated due to decreased plasma concentrations of voriconazole and possible loss of efficacy of the drug.

Astemizole, terfenadine Increased plasma concentrations of astemizole and terfenadine and, therefore, increased risk of serious arrhythmias due to these products.

Antigout medication Colchicine

Possibility of serious and/or life-threatening reactions in patients with renal insufficiency and/or hepatic insufficiency.

Concomitant use of ritonavir (500 mg twice daily) administered as an antiretroviral agent and rifabutin results in an increase in serum concentrations of rifabutin and the risk of adverse reactions, including uveitis.

Recommendations for the use of ritonavir administered as a pharmacokinetic enhancer with rifabutin are given in section 4.5.

Antipsychotics/Neuroleptics Lurasidone Increased plasma concentrations of lurasidone which may increase the risk of serious and/or life-threatening adverse reactions.

Clozapine, pimozide Increased plasma concentrations of clozapine and pimozide and, therefore, increased risk of serious hematological abnormalities or other serious adverse reactions due to these products.

Increased plasma concentrations of quetiapine which may lead to coma.

Concomitant administration with quetiapine is contraindicated.

Lopinavir and ritonavir is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir.

Lopinavir and ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or lifethreatening reactions. o Alpha 1-Adrenoreceptor Antagonist: alfuzosin o Antianginal: ranolazine o Antiarrhythmic: dronedarone o Anti-gout: colchicine o Antipsychotics: lurasidone, pimozide o Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine o GI Motility Agent: cisapride o Hepatitis C direct acting antiviral: elbasvir/grazoprevir o HMG-CoA Reductase Inhibitors: lovastatin, simvastatin o Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide o PDE5 Inhibitor: sildenafil (Revatio®) when used for the treatment of pulmonary arterial hypertension o Sedative/Hypnotics: triazolam, orally administered midazolam Lopinavir and ritonavir is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. o Anticancer Agents: apalutamide o Antimycobacterial: rifampin o Herbal Products: St.

John's Wort (hypericum perforatum) Hypersensitivity to lopinavir and ritonavir tablets (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) or any of its ingredients, including ritonavir.

Co-administration with drugs highly dependent on

CYP3A for clearance and for which elevated plasma levels may result in serious and/or lifethreatening events.

Co-administration with potent

CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross resistance.

May be taken with or without food, swallowed whole and not chewed, broken, or crushed.

Total recommended daily dosage is 800/200 mg given once or twice daily.

Lopinavir and ritonavir can be given as once daily or twice daily regimen.

Information for details.

Lopinavir and ritonavir once daily dosing regimen is not recommended in: Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.

In combination with carbamazepine, phenobarbital, or phenytoin.

In combination with efavirenz, nevirapine, or nelfinavir.

In pregnant women.

Patients (14 days and older) : Lopinavir and ritonavir once daily dosing regimen is not recommended in pediatric patients.

Twice daily dose is based on body weight or body surface area.

Concomitant Therapy in Adults and Pediatric Patients: Dose adjustments of lopinavir and ritonavir may be needed when co-administering with efavirenz, nevirapine, or nelfinavir.

Pregnancy: 400/100 mg twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.

There are insufficient data to recommend a lopinavir and ritonavir dose for pregnant patients with any documented lopinavir and ritonavir -associated resistance substitutions.

No dose adjustment of lopinavir and ritonavir is required for patients during the postpartum period. 2.1 General Administration Recommendations Lopinavir and ritonavir tablets may be taken with or without food.

The tablets should be swallowed whole and not chewed, broken, or crushed. 2.3 Dosage Recommendations in Adults Lopinavir and ritonavir can be given in once daily or twice daily dosing regimen at dosages noted in Tables and 2.

• Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.

• In combination with carbamazepine, phenobarbital, or phenytoin.

• In combination with efavirenz, nevirapine, or nelfinavir.

• In pediatric patients younger than 18 years of age.

Table 1.

Recommended Dosage in Adults -Lopinavir And Ritonavir Once Daily Regimen Lopinavir And Ritonavir Dosage Form Recommended Dosage 200 mg/50 mg Tablets 800 mg/200 mg (4 tablets) once daily Table 2.

Recommended Dosage in Adults -Lopinavir And Ritonavir Twice Daily Regimen Lopinavir And Ritonavir Dosage Form Recommended Dosage 200 mg/50 mg Tablets 400 mg/100 mg (2 tablets) twice daily The dose of lopinavir and ritonavir must be increased when administered in combination with efavirenz, nevirapine or nelfinavir.

Table 3 outlines the dosage recommendations for twice daily dosing when lopinavir and ritonavir is taken in combination with these agents.

Table 3.

Recommended Dosage in Adults -Lopinavir And Ritonavir Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or Nelfinavir Lopinavir And Ritonavir Dosage Form Recommended Dosage 200 mg/50 mg Tablets and 100 mg/25 mg Tablets 500 mg/125 mg (2 tablets of 200 mg/50 mg + 1 tablet of 100 mg/25 mg) twice daily 2.4 Dosage Recommendations in Pediatric Patients Lopinavir and ritonavir tablets are not recommended for once daily dosing in pediatric patients younger than 18 years of age.

Lopinavir and ritonavir 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet.

Calculate the appropriate dose of lopinavir and ritonavir for each individual pediatric patient based on body weight (kg) or body surface area (BSA) to avoid underdosing or exceeding the recommended adult dose.

Body surface area (BSA) can be calculated as follows: The lopinavir and ritonavir dose can be calculated based on weight or BSA: Based on Weight: Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered lopinavir dose (mg) Based on BSA: Patient BSA (m 2 ) × Prescribed lopinavir dose (mg/m 2 ) = Administered lopinavir dose (mg) Tablet Dosage Recommendation in Pediatric Patients Older than 6 Months to Less than 18 Years: Table 5 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for lopinavir and ritonavir tablets.

Table 5.

Lopinavir And Ritonavir Tablet Daily Dosage Recommendations in Pediatric Patients > 6 Months to < 18 Years of Age Without Concomitant Efavirenz, Nevirapine, or Nelfinavir Body Weight (kg) Body Surface Area (m2) * Recommended number of 100/25 mg Tablets Twice Daily ≥15 to 25 ≥0.6 to < 0.9 2 >25 to 35 ≥0.9 to < 1.4 3 >35 ≥1.4 4 Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir Dosing recommendations using tablets Table 7 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for lopinavir and ritonavir tablets when given in combination with efavirenz, nevirapine, or nelfinavir.

Table 7.

Lopinavir And Ritonavir Tablet Daily Dosage Recommendations for Pediatric Patients > 6 Months to < 18 Years of Age With Concomitant Efavirenz†, Nevirapine, or Nelfinavir† Body Weight (kg) Body Surface Area (m2) Recommended number of 100/25 mg Tablets Twice Daily ≥15 to 20 ≥0.6 to < 0.8 2 >20 to 30 ≥0.8 to < 1.2 3 >30 to 45 ≥1.2 to < 1.7 4 >45 ≥1.7 5 † Please refer to the individual product labels for appropriate dosing in children. 288 2.5 Dosage Recommendations in Pregnancy Administer 400/100 mg of lopinavir and ritonavir twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.

Once daily lopinavir and ritonavir dosing is not recommended in pregnancy.

There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions.

No dosage adjustment of lopinavir and ritonavir is required for patients during the postpartum period.

Tablets, USP 100 mg/25 mg are pale yellow colored capsule shaped, biconvex film-coated tablets debossed with ‘M31’ on one side and plain on other side.

Bottles of 60 tablets ….…………… (NDC 33342-163-09) Lopinavir and Ritonavir Tablets, USP 200 mg/50 mg are yellow colored, capsule shaped, biconvex, film-coated tablets debossed with ‘M32’ on one side and plain on other side.

Bottles of 120 tablets ….………… (NDC 33342-164-54) Recommended Storage: Store lopinavir and ritonavir tablets at 20°-25°C (68°77°F); excursions permitted to 15°-30°C (59°-86°F) .

Dispense in original container or

USP equivalent tight container.

For patient use: exposure of this product to high humidity outside the original container or USP equivalent tight container for longer than 2 weeks is not recommended.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lopinavir and ritonavir during pregnancy.

Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) .

The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%.

The background risk for major birth defects and miscarriage for the indicated population is unknown.

Methodological limitations of the APR include the use of MACDP as the external comparator group.

MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.

No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses.

Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period Administer 400/100 mg of lopinavir and ritonavir twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.

There are insufficient data to recommend lopinavir and ritonavir dosing for pregnant patients with any documented lopinavir-associated resistance substitutions.

No dose adjustment of lopinavir and ritonavir is required for patients during the postpartum period.

Once daily lopinavir and ritonavir dosing is not recommended in pregnancy.

Avoid use of lopinavir and ritonavir oral solution during pregnancy due to the ethanol content.

Lopinavir and ritonavir oral solution contains the excipients ethanol, approximately 42% (v/v and propylene glycol, approximately 15%. Data Human Data Lopinavir and ritonavir was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial. No new trends in the safety profile were identified in pregnant women dosed with lopinavir and ritonavir compared to the safety described in non-pregnant adults, based on the review of these limited data. Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program.

The prevalence of birth defects in live births was 2.1% (95% CI: 1.4%-3.0%) following first-trimester exposure to lopinavir-containing regimens and 3.0% (95% CI: 2.4%-3.8%) following second and third trimester exposure to lopinavir-containing regimens.

Based on prospective reports from the

APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP).

The prevalence of birth defects in live births was 2.2% (95% CI: 1.7%-2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%-3.6%) following second and third trimester exposure to ritonavir-containing regimens.

For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems.

Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats administered lopinavir in combination with ritonavir (on gestation days 6-17) at a maternally toxic dosage.

Based on

AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7 times (for lopinavir) and 1.8 times (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

In a pre-and post-natal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred.

No embryonic and fetal developmental toxicities were observed in rabbits administered lopinavir in combination with ritonavir (on gestation days 6-18) at a maternally toxic dosage.

AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6 times (for lopinavir) and similar to (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

Females and Males of Reproductive Potential Contraception Use of lopinavir and ritonavir may reduce the efficacy of combined hormonal contraceptives.

Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception.

The safety, efficacy, and pharmacokinetic profiles of lopinavir and ritonavir in pediatric patients below the age of 14 days have not been established.

Lopinavir and ritonavir should not be administered once daily in pediatric patients.

An open-label, multi-center, dose-finding trial was performed to evaluate the pharmacokinetic profile, tolerability, safety and efficacy of lopinavir and ritonavir oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m2 twice daily plus two NRTIs in HIVinfected infants ≥14 days and < 6 months of age.

Results revealed that infants younger than 6 months of age generally had lower lopinavir AUC12 than older children (6 months to 12 years of age), however, despite the lower lopinavir drug exposure observed, antiviral activity was demonstrated as reflected in the proportion of subjects who achieved HIV-1 RNA <400 copies/mL at Week 24.

Safety and efficacy in pediatric patients > 6 months of age was demonstrated in a clinical trial in 100 patients.

The clinical trial was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety, and efficacy of lopinavir and ritonavir oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve and experienced pediatric patients ages 6 months to 12 years.

Dose selection for patients 6 months to 12 years of age was based on the following results.

The 230/57.5 mg/m2 oral solution twice daily regimen without nevirapine and the 300/75 mg/m2 oral solution 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) .

A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose lopinavir and ritonavir with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m2 twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m2 twice daily+ ≥ 1 NRTI + 1 NNRTI) in 26 children and adolescents ≥ 2 years to < 18 years of age who had failed prior therapy.

Patients also had saquinavir mesylate added to their regimen.

This strategy was intended to assess whether higher than approved doses of lopinavir and ritonavir could overcome protease inhibitor cross-resistance.

High doses of lopinavir and ritonavir exhibited a safety profile similar to those observed in previous trials; changes in HIV-1 RNA were less than anticipated; three patients had HIV-1 RNA <400 copies/mL at Week 48.

CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks.

A prospective multicenter, randomized, open-label study evaluated the efficacy and safety of twice-daily versus once-daily dosing of lopinavir and ritonavir tablets dosed by weight as part of combination antiretroviral therapy (cART) in virologically suppressed HIV-1 infected children (n=173).

Children were eligible when they were aged < 18 years, ≥ 15 kg in weight, receiving cART that included lopinavir and ritonavir, HIV-1 ribonucleic acid (RNA) < 50 copies/mL for at least 24 weeks and able to swallow tablets.

At week 24, efficacy (defined as the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL) was significantly higher in subjects receiving twice daily dosing compared to subjects receiving once daily dosing.

The safety profile was similar between the two treatment arms although there was a greater incidence of diarrhea in the once daily treated subjects.

Clinical studies of lopinavir and ritonavir did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

In general, appropriate caution should be exercised in the administration and monitoring of lopinavir and ritonavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.