Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: RONIVID 400/50  
Dosage form and strength: Film coated tablet and 400 /50 mg  
APPROVED PROFESSIONAL INFORMATION FOR RONIVID  
WARNING:  
CO-ADMINISTRATION OF RONIVID WITH CERTAIN NON-SEDATING ANTIHISTAMINES, SEDATIVE  
HYPNOTICS, ANTI-DYSRHYTHMICS OR ERGOT ALKALOID PREPARATIONS MAY RESULT IN  
POTENTIALLY SERIOUS AND/OR LIFE-THREATENING ADVERSE EVENTS DUE TO POSSIBLE  
EFFECTS OF RONIVID ON THE HEPATIC METABOLISM OF THESE MEDICINES. SEE SECTIONS 4.3  
AND 4.4.  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
RONIVID 400/50 (film-coated tablet)  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each film-coated tablet of RONIVID contains darunavir ethanolate equivalent to 400 mg of darunavir and  
ritonavir USP 50 mg.  
Contains no sugar.  
‘for full list of excipients, see section 6.1’  
3 PHARMACEUTICAL FORM  
Yellow, capsule shaped, bevel edged and biconvex film coated tablets debossed with 'H' on one side and 'D8' on  
the other side.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
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RONIVID, in combination with other antiretroviral medicines, is indicated for the treatment of human  
immunodeficiency virus (HIV) infection in antiretroviral treatment experienced adult patients who are protease-  
inhibitor- naïve patients or after exclusion of darunavir resistance associated mutations (DRV-RAMs: V11I,  
V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V).  
Genotypic or phenotypic testing should guide the use of RONIVID.  
There is no information on the use of RONIVID in the paediatric population for the once daily dose.  
4.2 Posology and method of administration  
RONIVID must always be given in combination with other antiretroviral medicines.  
Posology  
Adults:  
Genotypic or phenotypic testing should guide the use of RONIVID. RONIVID 800/100 mg (two tablets) once daily  
dosing regimen is recommended in HIV protease- inhibitor-naïve patients and in treatment-experienced patients  
with demonstrated absence of DRV-RAMs. The ritonavir included in the formulation is used as a  
pharmacokinetic enhancer of darunavir (see Sections 4.5 and 5.2).  
Children (less than 12 years of age) and adolescents (12 to 17 years of age):  
The safety and efficacy of the once daily dose of RONIVID in paediatric patients have not been established.  
Missed Dose(s):  
In case a dose of RONIVID was missed within 12 hours of the time it is usually  
taken, patients should be instructed to take the prescribed dose of RONIVID with food as soon as possible. If this  
was noticed later than12 hours after the time it is usually taken, the missed dose should not be taken and the  
patient should resume the usual dosing schedule.  
Hepatic impairment:  
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No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data  
regarding the use of RONIVID when co-administered to patients with severe hepatic impairment; therefore,  
specific dosage recommendations cannot be made. RONIVID should not be used in patients with severe hepatic  
impairment as safety and efficacy have not been demonstrated (see section 4.4).  
Renal impairment:  
No dose adjustment is required in patients with renal impairment (see section 4.4 and 5.2).  
Method of administration  
Orally.  
RONIVID should be taken with food. The type of food does not affect the exposure to RONIVID.  
4.3 Contraindications  
Hypersensitivity to darunavir or ritonavir or to any of the excipients of RONIVID  
(listed in section 6.1).  
Darunavir and ritonavir are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. RONIVID should not be  
co-administered with medicines that are that are highly dependent on CYP3A for clearance and for which  
increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic  
index).  
These medicines are included in the table below:  
Medicines that are contraindicated with RONIVID  
Medicine Class:  
Medicine Name  
Anticonvulsants:  
Phenobarbitone  
Phenytoin  
Clinical Comment  
Phenobarbitone and phenytoin are inducers of CYP450 enzymes.  
RONIVID should not be used in combination with phenobarbitone, or  
phenytoin, as co-administration may cause significant decreases in  
darunavir plasma concentrations. This may result in loss of  
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therapeutic effect to RONIVID (see section 4.5).  
Antihistamines:  
Astemizole  
CONTRAINDICATED due to potential for serious and/or life-  
threatening reactions such as cardiac dysrhythmia.  
Antimycobacterial:  
Rifampicin  
Rifampicin is a potent inducer of CYP450 metabolism. RONIVID  
should not be used in combination with rifampicin, as this may cause  
significant decreases in darunavir plasma concentrations. This may  
result in loss of therapeutic effect to RONIVID (see section 4.5).  
The exposure to rifabutin and its active metabolite was increased 3-  
fold and the incidence of side effects was doubled when rifabutin was  
given at a dose of 150 mg every other day in combination with  
RONIVID (see section 4.5).  
Rifabutin  
Endothelin receptor  
antagonist:  
Concomitant use of bosentan and RONIVID shoud be avoided (see  
section 4.5).  
Bosentan  
PDE-5 inhibitor:  
A safe and effective dose of sildenafil for the treatment of pulmonary  
Sildenafil – when intended for the arterial hypertension has not been established. There is an increased  
treatment of pulmonary arterial potential for sildenafil-associated adverse events (including visual  
hypertension  
disturbances, hypotension, prolonged erection and syncope).  
Co-administration of RONIVID in patients with renal or hepatic  
impairment is contraindicated due to the potential risk of colchicine-  
induced toxic effects.  
Antigout:  
Colchicine in patients  
with hepatic or renal  
impairment  
Alpha 1-adrenoreceptor  
antagonist:  
Potential for serious and/or life-threatening reactions such as  
hypotension.  
Alfuzosin  
Ergot Derivatives:  
CONTRAINDICATED due to potential for serious and/or life-  
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Dihydroergotamine  
Ergonovine  
threatening reactions such as acute ergot toxicity characterized by  
peripheral vasospasm and ischemia of the extremities and other  
tissues.  
Ergotamine  
Methylergonovine  
GI Motility Agents:  
Cisapride  
CONTRAINDICATED due to potential for serious and/or life-  
threatening reactions such as cardiac dysrhythmia.  
It is not recommended to co-administer RONIVID with boceprevir or  
telaprevir (see section 4.5).  
Hepatitis C virus  
(HCV) direct-acting antivirals:  
NS3-4A protease inhibitors  
Boceprevir  
Telaprevir  
Herbal Products:  
St. John’s wort  
RONIVID should not be used concomitantly with products containing  
St. John’s wort (Hypericum perforatum) because coadministration  
may cause significant decreases in darunavir plasma concentrations.  
This may result in loss of therapeutic effect to RONIVID (see section  
4.5).  
(Hypericum perforatum)  
HMG-CoA reductase  
inhibitors:  
Potential for serious reactions such as risk of myopathy including  
rhabdomyolysis.  
Lovastatin  
Simvastatin  
Neuroleptic:  
CONTRAINDICATED due to the potential for serious and/or life-  
threatening reactions such as cardiac dysrhythmia.  
Pimozide  
Sedative/Hypnotics:  
Midazolam, Triazolam  
CONTRAINDICATED due to potential for serious and/or life-  
threatening reactions such as prolonged or increased sedation or  
respiratory depression.  
Antifungals:  
CONTRAINDICATED because concomitant systemic use of  
ketoconazole, itraconazole or voriconazole and RONIVID may  
Ketoconazole  
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Itraconazole  
Voriconazole  
increase plasma concentrations of darunavir.  
Simultaneously, plasma concentrations  
of  
ketoconazole  
or  
itraconazole may be increased by RONIVID, while the plasma  
concentrations of voriconazole may be decreased in the presence of  
RONIVID (see section 4.5).  
Buprenorphine/  
naloxone  
The  
results  
of  
an  
interaction  
trial  
with  
RONIVID  
and  
buprenorphine/naloxone demonstrated that buprenorphine exposure  
was not affected when buprenorphine/naloxone was administered  
with RONIVID. Exposure of the active metabolite, norbuprenorphine,  
increased by 46 %. No dose adjustment for buprenorphine was  
required. Careful clinical monitoring is recommended if RONIVID and  
buprenorphine are co-administered (see section 4.5).  
Antidysrhythmics:  
Amiodarone  
Bepridil  
CONTRAINDICATED with RONIVID due to potential cardiac  
dysrhythmias.  
Flecainide  
Propafenone  
Quinidine  
Encainide  
Digoxin  
Antipsychotic:  
Blonanserin  
May result in potential increase in frequency or intensity of known  
neurological or other toxicities associated with blonanserin.  
Long-acting beta-adrenoceptor May result in potential increased risk of cardiovascular adverse  
agonist:  
events associated with salmeterol.  
Salmeterol  
4.4 Special warnings and precautions for use  
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Patients should be advised that current antiretroviral therapy, including RONIVID, does not prevent the risk of  
transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should  
continue to be employed.  
Elderly  
As limited information is available on the use of RONIVID in patients aged 65 and over, caution should be  
exercised in the administration of RONIVID in elderly patients, reflecting the greater frequency of decreased  
hepatic function and of concomitant disease or other therapy (see section 5.2).  
General  
RONIVID must be co-administered with food to exert its therapeutic effect (see section 4.2). Failure to correctly  
administer RONIVID with food will result in reduced plasma concentrations of darunavir that will be insufficient to  
achieve the desired antiviral effect.  
Severe skin reactions  
During the clinical development program, severe skin reactions, which may be accompanied with fever and/or  
elevations of transaminases, have been reported. Stevens-Johnson Syndrome has been reported; and during  
post-marketing experience toxic epidermal necrolysis has also been reported. RONIVID should be discontinued  
immediately if signs or symptoms of severe skin reactions develop.  
These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue,  
muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. Rash (all grades,  
regardless of causality) occurred in 10,3 % of patients treated with RONIVID. The discontinuation rate due to  
rash in patients using RONIVID was 0,5 %.  
Rash occurred more commonly in treatment-experienced patients receiving regimens containing RONIVID +  
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raltegravir compared to patients receiving RONIVID without raltegravir or raltegravir without RONIVID. However,  
rash that was considered medicine related occurred at similar rates for all three groups.  
Sulpha allergy  
Darunavir contains a sulphonamide moiety. RONIVID should be used with caution in patients with a known  
sulphonamide allergy.  
Patients with coexisting conditions  
Hepatic impairment  
RONIVID should not be used in patients with severe hepatic impairment. No dose adjustment is required in  
patients with mild or moderate hepatic impairment (see section 4.2 and 5.2).  
Hepatotoxicity  
Medicine-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with  
RONIVID. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an  
increased risk for liver function abnormalities including severe hepatic adverse events.  
Appropriate laboratory testing should be conducted prior to initiating therapy with RONIVID and patients should  
be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying  
chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during  
the first several months of RONIVID treatment.  
Evidence of new or worsening liver dysfunction (including clinically significant elevation of  
liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, liver tenderness, hepatomegaly) in  
patients on RONIVID should prompt consideration of interruption or discontinuation of treatment.  
Renal impairment  
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Since the renal clearance of darunavir is limited, a decrease in the elimination of RONIVID is not expected in  
patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that  
they will be significantly removed by haemodialysis or peritoneal dialysis (see section 4.2 and 5.2).  
Haemophilia patients  
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 such as RONIVID. In some patients  
additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was  
continued or reintroduced. A causal relationship has been postulated, although a mechanism of action has not  
been established. Haemophilia patients should therefore be made aware of the possibility of increased bleeding.  
Diabetes Mellitus/Hyperglycaemia  
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and  
hyperglycaemia have been reported during post- marketing surveillance in HIV infected patients receiving  
protease inhibitor therapy such as RONIVID. Some patients  
required either initiation or dose adjustment of insulin or oral hypoglycaemic medicines for treatment of these  
events. In some cases, diabetic ketoacidosis has occurred. Patients who discontinued protease inhibitor  
therapy, the hyperglycaemia persisted in some cases.  
Lipodystrophy and metabolic abnormalities  
Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including  
central obesity, dorso-cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast  
enlargement, and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include  
evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough  
cardiovascular risk assessment.  
Immune Reconstitution Inflammatory Syndrome  
Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid  
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restoration of pathogen-specific immune responses to pre-existing antigens combined with immune  
dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically such  
reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an  
asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops  
within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts.  
Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and  
cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued and  
ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to  
glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune  
disorders (such as Graves' disease) have also been reported as IRIS reactions; however, the reported time to  
onset is more variable and these events can occur many months after initiation of treatment.  
Osteonecrosis  
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption,  
severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in  
patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (cART).  
Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or  
difficulty in movement.  
Opportunistic infections  
Patients receiving RONIVID should be advised that they may continue to develop opportunistic infections and  
other complications of HIV infection, and therefore they should remain under close observation by healthcare  
professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral  
load and CD4 counts needs to be done.  
Interactions with medicines  
Darunavir and ritonavir are both inhibitors of CYP3A. Co- administration of [PRODUCT  
NAME] with medicines primarily metabolised by CYP3A may result in increased plasma concentrations of such  
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medicines, which could increase or prolong their therapeutic effect  
and adverse events (see section 4.3 and 4.5). For medicines that are highly dependent on  
the metabolism by CYP3A and that have a narrow therapeutic index, such as amiodarone,  
bepridil, (systemic) lidocaine and quinidine, plasma concentrations of such medicines could increase when  
combined with RONIVID. This can lead to prolongation or increase of their therapeutic effect and adverse events  
(see section 4.5).  
HMG-CoA Reductase Inhibitors  
The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on  
CYP3A for metabolism, thus concomitant use of RONIVID with simvastatin or  
lovastatin is contraindicated due to an increased risk of myopathy including rhabdomyolysis. Caution must be  
exercised and reduced doses should be considered if RONIVID is used concurrently with atorvastatin, which is  
metabolised to a lesser extent by CYP3A4. While rosuvastatin elimination is not dependent on CYP3A, an  
elevation of rosuvastatin exposure has been reported with RONIVID co-administration. If treatment with an HMG-  
CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see TABLE 2).  
Methadone  
No adjustment of methadone dosage is required when initiating co-administration of  
RONIVID. However, clinical monitoring is recommended as maintenance therapy may need to be adjusted (see  
section 4.5).  
Oestrogen-based contraceptives  
Plasma concentrations of ethinylestradiol are decreased by induction of its metabolism by  
ritonavir and alternative methods of non-hormonal contraception are recommended (see  
section 4.5).  
PDE 5 Inhibitors  
Caution should be used when prescribing sildenafil, tadalafil or vardenafil for the treatment of erectile dysfunction  
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or pulmonary hypertension in patients receiving RONIVID. Co-administration of RONIVID with these medicines is  
expected to increase their concentrations and may result in increased associated adverse events, such as  
hypotension and prolonged erection. Concomitant use of sildenafil with RONIVID is contraindicated in pulmonary  
arterial hypertension patients (see section 4.3 and 4.5).  
Ritonavir  
Pancreatitis  
Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed  
hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be  
at increased risk of elevated triglycerides and pancreatitis. Pancreatitis should be considered if clinical symptoms  
(nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or  
amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should  
be evaluated and ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.  
Corticosteroids  
Concomitant use of RITONAVIR and fluticasone propionate can significantly increase fluticasone propionate  
plasma concentrations and reduce serum cortisol concentrations.  
Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported when  
RITONAVIR has been co-administered with inhaled or intranasally administered fluticasone propionate. Similar  
findings with concomitant administration of RITONAVIR and other inhaled corticosteroids that are metabolised  
similarly to fluticasone, such as budesonide, cannot be excluded. Particular caution should  
be used when administering RITONAVIR and any of these inhaled or intranasally administered glucorticoids (see  
section 4.5).  
Herbal Products  
Patients on RITONAVIR should not use products containing St. John’s Wort (Hypericum perforatum) because  
co-administration may be expected to reduce plasma concentrations of ritonavir. This may result in loss of  
therapeutic effect and development of resistance (see section 4.3 and 4.4).  
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Resistance/Cross-Resistance  
Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of  
RITONAVIR therapy following loss of viral suppression may increase the likelihood of cross-resistance to other  
protease inhibitors.  
The potential for HIV cross-resistance between protease inhibitors has not been fully explored. Therefore, it is  
unknown what effect RITONAVIR therapy will have on the activity of concordantly or subsequently administered  
protease inhibitors.  
Laboratory Tests  
RITONAVIR has been associated with alterations in triglycerides, ALT, AST, GGT, CPK and uric acid.  
Appropriate laboratory testing should be performed prior to initiating RITONAVIR therapy and at periodic  
intervals or if any clinical signs or symptoms occur during therapy. For comprehensive information concerning  
laboratory test alterations associated with nucleoside analogues, medical practitioner should refer to the  
complete product information for each of these medicines.  
PR Interval Prolongation  
Ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some patients.  
Reports of second or third degree atrioventricular block in patients with underlying structural heart disease and  
pre-existing conduction system abnormalities or in  
patients receiving medicines known to prolong the PR interval (such as verapamil or atazanavir) have been  
reported in patients receiving RITONAVIR.RITONAVIR should be  
used with caution in such patients.  
Fat Redistribution  
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump),  
peripheral wasting, breast enlargement and “cushingoid appearance” have been observed in patients receiving  
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protease inhibitors.  
Lipid Disorders  
Treatment with RITONAVIR therapy in combination with saquinavir has resulted in substantial increases in the  
concentration of total triglycerides and cholesterol. Triglyceride  
and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during  
therapy. Lipid disorders should be managed as clinically appropriate. See TABLE 2 for additional information on  
potential medicine interactions with RITONAVIR and HMG-CoA Reductase Inhibitors (hypolipidemics).  
4.5 Interaction with other medicines and other forms of interaction  
Darunavir and ritonavir are both inhibitors of the cytochrome CYP3A. Co-administration of  
RONIVID with medicines primarily metabolised by CYP3A may result in increased plasma concentrations of  
such medicines, which could increase or prolong their therapeutic effect and adverse events.  
RONIVID should not be co-administered with medicines that are highly dependent on CYP3A for clearance and  
for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow  
therapeutic index). These medicines include astemizole, alfuzosin, sildenafil (when used for treatment of  
pulmonary arterial hypertension), midazolam, triazolam, pimozide and the ergot alkaloids (e.g. ergotamine,  
dihydroergotamine, ergonovine and methylergonovine) (see section 4.3).  
Rifampicin is a potent inducer of CYP450 metabolism. RONIVID should not be used in combination with  
rifampicin, as co- administration may cause significant decreases in darunavir plasma concentrations. This may  
result in loss of therapeutic effect to RONIVID (see section 4.3 and 4.5).  
RONIVID should not be used concomitantly with products containing St. John’s Wort (Hypericum perforatum)  
because co-administration may cause significant decreases in darunavir and ritonavir plasma concentrations.  
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This may result in loss of therapeutic effect to RONIVID (see section 4.3 and 4.4).  
Antiretroviral medicines  
Nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs)  
Didanosine  
RONIVID (600/100 mg twice daily) did not significantly affect didanosine exposure. The combination of RONIVID  
and didanosine can be used without dose adjustments. As it is recommended that didanosine be administered  
on an empty stomach, didanosine should be administered1 hour before or 2 hours after RONIVID (which are  
administered with food).  
Tenofovir  
The results of an interaction trial with tenofovir (tenofovir disoproxil fumarate 300 mg once  
daily) demonstrated that the systemic exposure of tenofovir was increased by 22 % when co-administered with  
RONIVID (300/100 mg twice daily). This finding is not considered to be clinically relevant. There was no change  
in the urinary excretion of tenofovir or darunavir during co-administration. Tenofovir did not have a clinically  
significant influence on darunavir exposure. No dose adjustments of darunavir, ritonavir, or tenofovir disoproxil  
fumarate are required when these medicines are co-administered.  
Other NRTIs  
Based on the different elimination pathways of other NRTSs such as zidovudine, zalcitabine emtricitabine,  
stavudine, lamivudine and abacavir that are primarily renally excreted, no medicine interactions are expected for  
these medicines and RONIVID.  
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)  
Etravirine  
In an interaction trial between RONIVID (600/100 mg twice daily) and etravirine,  
there was a 37 % decrease in etravirine exposure in the presence of RONIVID and no relevant change in  
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exposure to darunavir. Therefore, RONIVID can be co-administered with etravirine 200 mg twice daily without  
dose adjustments.  
Efavirenz  
An interaction trial between RONIVID (300/100 mg twice daily) and efavirenz 600 mg once daily) has been  
performed. In the presence of efavirenz, a decrease of 13 % for darunavir exposure and a decrease of darunavir  
Cmin by 31 % were observed. Exposure to efavirenz was increased by 21 % when administered in combination  
with RONIVID. The combination of RONIVID and efavirenz should be used with caution.  
Nevirapine  
The results of an interaction trial with [PORODUCT NAME] 400/100 mg twice daily) and  
nevirapine (200 mg twice daily) demonstrated that darunavir exposure was not affected when administered  
concomitantly with nevirapine. Exposure to nevirapine increased by 27 % (compared to historical controls) when  
administered in combination with RONIVID. Since this difference is not considered to be clinically relevant, the  
combination of RONIVID and nevirapine can be used without dose adjustments.  
Rilpivirine  
In an interaction trial between RONIVID (800/100 mg once daily) and rilpivirine  
(150 mg once daily), no clinically relevant effect on darunavir exposure was observed. Exposure to rilpivirine  
increased by 130 % (2,3-fold) when administered in combination with RONIVID. Since this difference is not  
considered to be clinically relevant, the combination of RONIVID and rilpivirine can be used without dose  
adjustments.  
HIV protease inhibitors (PIs)  
Ritonavir  
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the  
systemic exposure of darunavir when a single dose of 600 mg was given orally in combination with ritonavir at  
100 mg twice daily. Therefore, darunavir should only be used in combination with low dose ritonavir as a  
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pharmacokinetic enhancer (see section 4.4 and 5.2).  
Lopinavir/ritonavir  
Results of interaction trials with darunavir with or without ritonavir and lopinavir/ritonavir (1 200 mg darunavir  
twice daily with or without 100 mg ritonavir twice daily and lopinavir/ritonavir 400/100 mg twice daily or 533/133,3  
mg twice daily) demonstrated a decrease in the exposure (AUC) of darunavir by 40 %. The appropriate doses of  
the combination have not been established. Hence, it is not recommended to co-administer RONIVID with  
lopinavir/ritonavir.  
Saquinavir  
In an interaction trial between darunavir (400 mg twice daily), saquinavir (1 000 mg twice daily) and ritonavir (100  
mg twice daily), darunavir exposure was decreased by 26 % in the presence of saquinavir/rtv; saquinavir  
exposure was not affected by the presence of RONIVID. It is not recommended to combine saquinavir and  
darunavir, with or without low dose ritonavir.  
Atazanavir  
An interaction trial between RONIVID (400/100 mg twice daily) and atazanavir (300 mg once daily) demonstrated  
that systemic exposure to darunavir and atazanavir was not significantly affected when co-administered.  
Atazanavir can be co- administered with  
RONIVID.  
Indinavir  
In an interaction trial between RONIVID (400/100 mg twice daily) and indinavir (800 mg twice daily), darunavir  
exposure was increased by 24 % in the presence of indinavir/rtv; indinavir exposure was increased by 23 % in  
the presence of RONIVID.  
Other HIV protease inhibitors  
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The co-administration of RONIVID and PIs other than lopinavir/ritonavir, saquinavir, atazanavir and indinavir has  
not been studied. Therefore, such co-administration is not recommended.  
CCR5 antagonist  
When used in combination with RONIVID, the dose of maraviroc should be 150 mg twice daily. An interaction  
trial between RONIVID (600/100 mg twice daily) and maraviroc (150 mg twice daily) demonstrated that in the  
presence of RONIVID the exposure of maraviroc was increased 4-fold. There was no apparent effect of  
maraviroc on darunavir/ritonavir exposure.  
Other medicines:  
Alfuzosin  
Exposure to alfuzosin may be increased when co-administered with RONIVID.  
Concomitant use of RONIVID with alfuzosin is contraindicated (see section 4.3).  
Antidysrhythmics (bepridil, systemic lidocaine, quinidine and amiodarone)  
Exposure to bepridil, lidocaine, quinidine and amiodarone may be increased when co-administered with  
RONIVID. Caution is warranted and therapeutic medicine monitoring of antidysrhythmics is recommended when  
darunavir is administered with antidysrhythmic medicines.  
Digoxin  
An interaction trial with RONIVID (600/100 mg twice daily) and a single dose of  
digoxin (0,4 mg) showed an increase of digoxin AUClast of 77 % (ratio of Least Square Means (LSM) was 1,77  
with a 90 % CI of 0,90 to 3,50). It is recommended that the lowest dose of digoxin should initially be prescribed  
and digoxin dose should be titrated to obtain the desired clinical effect when co-administered with RONIVID.  
Serum digoxin concentrations should be monitored to assist in the titration.  
Anticoagulants  
Warfarin concentrations may be affected (decreased) when co- administered with RONIVID. It is recommended  
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that the international normalized ratio (INR) be monitored when warfarin is combined with [PPRODUCT NAME].  
Anticonvulsants (phenobarbitone, phenytoin and carbamazepine)  
Phenobarbitone and phenytoin  
Phenobarbitone and phenytoin are inducers of CYP450 enzymes. RONIVID should not be used in combination  
with these medicines, as co-administration may cause significant decreases in darunavir plasma concentrations.  
This may result in loss of therapeutic effect to darunavir (see section 4.3).  
Carbamazepine  
An interaction trial between RONIVID (600/100 mg twice daily) and carbamazepine (200 mg twice daily) showed  
that the exposure to darunavir, co-administered with ritonavir, was unaffected by carbamazepine. Ritonavir  
exposure (AUC12h) was decreased by 49 %. For carbamazepine, AUC12h was increased by 45 %. No dose  
adjustment for RONIVID is recommended. If there is a need to combine RONIVID and carbamazepine, patients  
should be monitored for potential carbamazepine related adverse events. Carbamazepine concentrations should  
be monitored and its dose should be titrated for adequate response. Based upon the findings, the  
carbamazepine dose may need to be reduced by 25 % to 50 % in the presence of RONIVID.  
Antimalarials  
An interaction trial between RONIVID (600/100 mg twice daily) and artemether/lumefantrine (80/480 mg, 6 doses  
at 0, 8, 24, 36, 48, and 60 hours) showed an  
increase in exposure to lumefantrine by 2,75-fold, while exposure to darunavir was not affected. The exposure to  
artemether and its active metabolite, dihydroartemisinin, decreased by 16 % and 18 %, respectively. The  
combination of darunavir and artemether/  
lumefantrine can be used without dose adjustments; however, due to the increase in lumefantrine exposure, the  
combination should be used with caution.  
Colchicine  
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Concomitant use of colchicine and RONIVID may increase the exposure to colchicine. The following dose  
adjustments are recommended for colchicine. For the treatment of gout flares in patients on RONIVID, the  
recommended dose of colchicine is 0,5 mg (1 tablet), followed by 0,25 mg 1 hour later. Treatment course to be  
repeated no earlier than 3 days. For the prophylaxis of gout flares in patients on RONIVID, the recommended  
dose of colchicine is 0,25 mg every day or every other day. For the treatment of familial Mediterranean fever in  
patients on RONIVID, the maximum dose of colchicine is0,5 mg every day (may be given as0,25 mg twice daily).  
Patients with renal or hepatic impairment should not be given colchicine with RONIVID.  
Antihistamines (Astemizole)  
Exposure to these antihistamines may be increased when co- administered with RONIVID. Concomitant use of  
RONIVID with astemizole is contraindicated (see section 4.3).  
Calcium channel blockers  
The exposure to calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when RONIVID  
are used concomitantly. Caution is warranted and careful clinical monitoring is recommended.  
Clarithromycin  
An interaction trial between RONIVID (400/100 mg twice daily) and clarithromycin (500 mg twice daily) showed  
an increase in exposure to clarithromycin by 57 %, while exposure to darunavir was not affected. For patients  
with renal impairment, a dose reduction of clarithromycin should be considered. For patients with renal  
impairment, the following dose adjustments should be considered:  
- For patients with CLcr of 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50 %.  
- For patients with CLcr of < 30 ml/min, the dose of clarithromycin should be reduced by 75 %.  
Dexamethasone  
Systemic dexamethasone induces CYP3A and thereby may decrease darunavir exposure. This may result in  
loss of therapeutic effect. Therefore, this combination should be used with caution.  
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Bosentan  
Bosentan is metabolised by cytochrome CYP3A4 and CYP2C9. Concomitant use of bosentan and darunavir  
should be avoided (see section 4.3).  
Fluticasone  
Concomitant use of inhaled fluticasone and RONIVID may increase plasma concentrations of fluticasone.  
Alternatives should be considered, particularly for long term use.  
Hepatitis C virus (HCV) direct-acting antivirals:  
NS3-4A protease inhibitors  
Boceprevir  
In an interaction trial between RONIVID (600/100 mg twice daily) and boceprevir (800 mg three times daily),  
darunavir exposure was reduced by 44 % and boceprevir exposure was reduced by 32 %. It is not recommended  
to co-administer RONIVID with boceprevir (see section 4.3).  
Telaprevir  
In an interaction trial between RONIVID (600/100 mg twice daily) and telaprevir (750 mg every 8 hours),  
darunavir exposure was reduced by 40 % and telaprevir exposure was reduced by 35 %. It is not recommended  
to co-administer RONIVID with telaprevir (see section 4.3).  
HMG CoA reductase inhibitors  
HMG CoA reductase inhibitors, such as lovastatin and simvastatin, which are highly dependent on CYP3A  
metabolism, are therefore expected to have markedly increased plasma concentrations when co-administered  
with RONIVID. Increased concentrations of HMG CoA reductase inhibitors may cause myopathy, including  
rhabdomyolysis. Concomitant use of RONIVID with lovastatin and simvastatin is therefore not recommended  
(see section 4.3). The results of an interaction trial with atorvastatin show that atorvastatin (10 mg once daily) in  
combination with RONIVID (300/100 mg twice daily) provides an exposure to atorvastatin, which is only 15 %  
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lower than that obtained with atorvastatin (40 mg once daily) alone. When administration of  
atorvastatin and RONIVID is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A  
gradual dose increase of atorvastatin may be tailored to the clinical response.  
RONIVID (600/100 mg twice daily) increased exposure to a single dose of pravastatin (40 mg) by approximately  
80 %, but only in a subset of patients. When administration of pravastatin and RONIVID is required, it is  
recommended to start with the lowest possible dose of pravastatin and titrate up to the desired monitoring safety  
(see section 4.4). An interaction study evaluating RONIVID (600/100 mg twice daily) in combination with  
rosuvastatin (10 mg once daily) resulted in a 50 % increase in rosuvastatin exposure. It is recommended to start  
with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for  
safety.  
H2 Receptor antagonists and proton pump inhibitors  
Co-administration of omeprazole (20 mg once daily) or ranitidine (150 mg twice daily) and PRODUCT NAME]  
(400/100 mg once daily) did not affect the exposure to darunavir. Based on these results, RONIVID can be co-  
administered with H2 receptor antagonists and proton pump inhibitors without dose adjustments.  
Inhaled beta agonist (salmeterol)  
Concomitant use of salmeterol and RONIVID is not recommended. The combination may result in increased risk  
of cardiovascular adverse events with salmeterol, including QT prolongation, palpitations and sinus tachycardia.  
Immunosuppressants (ciclosporin, tacrolimus, sirolimus)  
Exposure to ciclosporin, tacrolimus, or sirolimus may be increased when co-administered with RONIVID.  
Therapeutic drug monitoring of the immunosuppressive agent is recommended when co-administered with  
RONIVID.  
Ketoconazole, itraconazole and voriconazole  
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Ketoconazole, itraconazole and voriconazole are potent inhibitors as well as substrates of CYP3A.Concomitant  
systemic use of ketoconazole, itraconazole or voriconazole and RONIVID may increase plasma concentrations  
of darunavir. Simultaneously, plasma concentrations of ketoconazole or itraconazole may be increased by  
RONIVID. This was confirmed in an interaction trial where the concomitant administration of ketoconazole (200  
mg twice daily) with RONIVID (400/100 mg twice daily) increased exposure of ketoconazole and darunavir by  
212 % and 42 %, respectively. Concomitant use of ketoconazole, itraconazole and voriconazole with darunavir is  
contraindicated (see section 4.3).  
Methadone  
An interaction trial investigating the effect of RONIVID (600/100 mg twice daily) on a stable methadone  
maintenance therapy showed an AUC decrease of 16 % for R-methadone. Based on pharmacokinetic and  
clinical findings, no adjustment of methadone dosage is required when initiating co-administration of RONIVID.  
However, clinical monitoring is recommended as maintenance therapy may need to be adjusted in some patients  
(see section 4.4).  
Buprenorphine/ naloxone  
The results of an interaction trial with RONIVID and buprenorphine/naloxone demonstrated that buprenorphine  
exposure was not affected when administered with RONIVID. Exposure of the active metabolite,  
norbuprenorphine, increased by 4 %. No dose adjustment for buprenorphine was required. Careful clinical  
monitoring is recommended if RONIVID and buprenorphine are co-administered.  
Oestrogen based contraceptives  
The results of an interaction trial between RONIVID (600/100 mg twice daily) and ethinylestradiol and  
norethindrone demonstrated that at steady state systemic exposures to ethinylestradiol and norethindrone are  
decreased by 44 % and 14%, respectively. Therefore, alternative methods of non-hormonal contraception should  
be used (see section 4.4).  
PDE-5 inhibitors  
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Treatment of erectile dysfunction  
In an interaction trial a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg  
sildenafil alone and a single intake of 25 mg sildenafil co-administered with RONIVID (400/100 mg twice daily).  
Concomitant use of PDE-5 inhibitors for the treatment of erectile dysfunction with RONIVID should be done with  
caution. If concomitant use of RONIVID with sildenafil, vardenafil, or tadalafil is indicated, sildenafil at a single  
dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2,5 mg dose in 72hours or  
tadalafil at a single dose not exceeding 10 mg dose in 72 hours is recommended (see section 4.4).  
Treatment of pulmonary arterial hypertension  
A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension has not been  
established. There is an increased potential for sildenafil associated adverse events (including visual  
disturbances, hypotension, prolonged erection and syncope). Therefore, coadministration of RONIVID with  
sildenafil when used for pulmonary arterial hypertension is contraindicated (see section 4.3). For the treatment of  
pulmonary arterial hypertension with tadalafil co-administered with RONIVID, a dose adjustment for tadalafil is  
warranted. In patients who have been receiving RONIVID for at least 1 week, start tadalafil at 20 mg,once daily  
and increase to 40 mg once daily based upon individual tolerability. For patients on tadalafil and initiating  
RONIVID, discontinue the use of tadalafil at least 24 hours prior to initiating RONIVID and avoid the use use of  
tadalafil during the initiation of RONIVID. After at least 1 week following the initiation of RONIVID, resume  
tadalafil at 20 mg once daily and increase to 40 mg once daily based upon individual tolerability.  
Rifabutin  
Rifabutin is a substrate of CYP450 enzymes. In an interaction trial, an increase of systemic  
exposure to darunavir by 57 % was observed, when RONIVID (600/100 mg twice daily) was administered with  
rifabutin (150 mg once every other day). Based on the safety profile of RONIVID, the increase in darunavir  
exposure in the presence of rifabutin does not warrant a dose adjustment for RONIVID. The exposure to rifabutin  
(sum of main compound and its active metabolite) was increased 3-fold and the incidence of side effects was  
doubled when rifabutin was given at a dose of 150 mg every other day in combination with darunavir and  
ritonavir (see section 4.3).  
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Selective Serotonin Reuptake Inhibitors (SSRIs)  
In an interaction trial between paroxetine (20 mg once daily) or sertraline (50 mg once daily) and RONIVID  
(400/100 mg twice daily), the exposure to darunavir was not affected by the presence of sertraline or paroxetine.  
Exposure to sertraline and paroxetine, was decreased by 49 % and 39 %, respectively, in the presence of  
RONIVID. If SSRIs are co-administered with RONIVID, the recommended approach is a careful dose titration of  
the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of  
sertraline or paroxetine who start treatment with RONIVID should be monitored for antidepressant response.  
Ritonavir  
Medicines which increase CYP3A activity (e.g. phenobarbitone, carbamazepine, dexamethasone, phenytoin,  
rifampicin and rifabutin) would be expected to increase the clearance of ritonavir resulting in decreased ritonavir  
plasma concentrations.  
RITONAVIR has a high affinity for several cytochrome P450 (CYP) isoforms with the following ranked order:  
CYP3A4 > CYP2D6 > CYP2C9 > CYP2C19 >> CYP2A6, CYP1A2,  
CYP2E1. There is evidence that RITONAVIR may induce glucuronosyl transferase, CYP1A2, CYP2C9 and  
CYP2C19 enzymes. Decreased plasma concentrations of the other  
medicine and loss of therapeutic effects during RITONAVIR co-administration may signify the may signify the  
need for dosage alteration of these medicines.  
In addition to the medicines listed in the section 4.3, TABLE 2 summarises some commonly prescribed  
medicines, separated by the type of metabolism and expected magnitude of interaction when co-administered  
with ritonavir. Co-administration of RITONAVIR and medicines primarily metabolised by CYP3A may result in  
increased plasma concentrations of the other medicine, which could increase or prolong its therapeutic and  
adverse effects.  
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Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly  
administered with ritonavir. Dosage reductions may be required for those medicines extensively metabolised by  
CYP3A.  
Cardiac and neurologic events have been reported when RITONAVIR has been co-administered with  
disopyramide, mexiletine, nefazodone or fluoxetine. The possibility of interaction cannot be excluded.  
Table 2:  
Potential effects on medicines co-administered with RITONAVIR.  
(Contraindicated Medications are listed in Column 1)  
Medicine  
Category  
Representative Medicines by Potential  
Interaction Category  
Contraindi Large1  
cated  
Moderat  
e1  
Moderate1  
Possible  
Possible  
↑ AUC2  
↑ or ↓  
↓ AUC2  
↓ AUC2  
Medicatio  
↑ AUC2  
AUC2  
n
(CYP3A  
)
(Unknow (Glucuronidation)  
(CYP2D  
6)  
(CYP2C9/1 n CYP)  
9)  
Analgesics  
, narcotics  
Alfentan  
il  
Hydroco  
done  
Levamet  
hadyl  
Codeine  
Hydromorphone  
Meperidine*  
Methadone*  
Morphine  
(LAAM)  
Fentanyl Oxycodo  
ne  
Tramado  
l
Analgesics  
, non-  
Diclofenac  
Nabume  
tone  
Ketoprofen  
Ketorolac  
Flurbiprofe  
n
steroidal  
Sulindac  
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Ibuprofen  
Naproxen  
Indometha  
cin  
Piroxicam  
Antidysrhy  
thmic  
Amiodaro  
ne  
Lidocain  
e
Disopyra  
mide  
Tocainid  
e11  
Encainide  
Flecainide  
Mexiletin  
e
Propafen  
one  
Quinidine  
Digoxin  
Antiasthma  
tic  
Theophylline*  
Antibiotic,  
macrolide  
Erythro  
mycin  
Clarithro  
mycin*  
Antibiotic,  
steroidal  
Fusidic  
acid  
Anticovuls  
ant  
Carbam  
azepine  
Clonaze  
pam  
Phenob  
arbitone  
Divalproex  
Lamotrigine  
Phenytoin  
Ethosuxi  
mide  
Antidepres  
sant  
Amitripty  
line  
Doxepin  
11  
tricyclic  
Clomipra  
mine  
Desipra  
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mine*  
Imiprami  
ne  
Maprotili  
ne  
Nortriptyl  
ine  
Trimipra  
mine  
Antidepras  
santSSRIs  
and non-  
Nefazod  
one  
Fluoxeti  
ne  
Fluvoxa  
mine  
Bupropion  
Sertalin  
e
Paroxeti  
ne  
tricyclics  
Trazodo  
ne*  
Venlafax  
ine  
Antidiarrho  
eal  
Diphenoxylate  
Loperamide  
Antiemetic  
s
Cisapride  
Ondans  
etron  
Prochlor  
Metaclopramide  
perazine  
11  
Prokinetics  
Prometh  
azine  
Antifungal  
medicines  
Voriconza  
le  
Itracona  
zole  
Ketocon  
azole*  
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Miconaz  
ole  
Antihistami Astemizol  
Loratadi  
ne  
nes  
e
Antihypert  
ensive  
Bosenta  
n
Losartan  
Doxazos  
in 11  
Prazosin  
11  
Terazosi  
n11  
Antimyco-  
bacterial  
Rifabuti  
n*  
Ethiona  
mide  
Rifampic  
in  
Antiparasit  
ics  
Quinine  
Proguanil  
Albenda  
zole  
Atovaquone  
Chloroq  
uine  
Metronid  
azole  
Primaqui  
ne  
Pyrimeth  
amine  
Antipsycho Blonanser  
tics  
in  
Protein  
pump  
Lansopraz  
ole  
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inhibitors  
Omeprazol  
e
B-blockers  
Metoprol  
ol  
Propranolol Betaxolo  
l11  
Penbutol  
ol  
Pindolol  
Timolol  
β2-agonist  
(long  
Salmetero  
l
acting)  
Calcium  
channel  
blockers  
Bepridil  
Amlodipi  
ne  
Diltiaze  
m
Felodipi  
ne  
Isradipin  
e
Nicardip  
ine  
Nifedipi  
ne  
Nimodip  
ine  
Nisoldipi  
ne  
Nitrendi  
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pine  
Verapa  
mil  
Cancer  
Tamoxif  
en  
Etoposid  
e
Cyclophos  
phamide3  
Daunoru  
bicin11  
chemo  
therapeutic  
medicines  
Paclitax  
el  
Ifosfamide3  
Doxorub  
icin11  
Vinblasti  
ne  
Vincristi  
ne  
Ergot  
Dihydroer  
gotamine  
Bromicri  
ptine  
Methyse  
rgide11  
alkaloids  
and  
Ergonovin  
e
derivatives  
11  
Ergotamin  
e
Methylerg  
o-novine11  
Haemorhe  
ologic  
Pentoxif  
ylline  
agent  
Herbal  
St. John’s  
Products  
Wort  
HIV  
Atazana  
vir  
Maraviro  
c
Nevirapi  
ne11  
Antivirals  
Darunav  
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ir  
(fos)  
ampren  
avir  
Indinavir  
*
Saquina  
vir*  
Tiprana  
vir  
Hypo-  
Glimepiride  
Glipizide  
glycaemics  
Glyburide  
Tolbutamid  
e
Hypolipide  
mics  
Lovastatin Atorvast  
Rosuvas  
tatin  
Gemfibr  
ozil  
Clofibrate  
atin  
Simvastat  
in  
Immuno-  
suppressa  
nts  
Ciclospo  
rine  
Everoli  
mus  
Tacrolim  
us  
Sirolimu  
s
(rapamy  
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cin)  
Neurolepti  
cs  
Pimozide  
Chlorpro  
mazine  
Clozapine  
Haloperi  
dol  
Perphen  
azine  
Risperid  
one  
PDE5  
Sildenafil  
indicated  
for PAH  
Sildenafi  
l
inhibitor  
indicate  
d for ED  
Tadalafil  
Vardena  
fil  
Sedative/h  
ypnotics  
Midazola  
m
Buspiro  
ne  
Clorazep  
ate  
Lorazepam  
Oxazepam  
Propofol  
Triazolam  
Diazepa  
m
Temazepam  
Estazola  
m
Flurazep  
am  
Zolpide  
m
Steroids  
Dexame  
thasone  
Predniso  
ne  
Ethinyl  
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Fluticas  
one*  
Estradiol*  
Stimulants  
Dexfenfl  
uramine  
Methylp  
henidate  
Metham  
phetami  
ne  
1 Large = > 3X; Moderate = 1.5-3X  
2 AUC = area under the plasma concentration-time curve, a measure of medicine exposure.  
3
An increase in the AUC of cyclophosphamide and ifosfamide, both activated by CYP, may correspond  
to a decrease in the AUC of the active metabolite (s) and a possible decrease in efficacy of these  
medicines.  
11 A possible increase in concentration is more likely when combined with ritonavir.  
*Clinical medicine interaction study has been performed  
Alprazolam: Co-administration of alprazolam with RITONAVIR resulted in a statistically significant decrease in  
mean alprazolam Cmax values (16 %) but not in mean AUC values (12 %).  
Amprenavir: Literature reports have shown that concentrations of the HIV-protease inhibitor, amprenavir are  
increased when co-administered with RITONAVIR.  
Bosentan: Co-administration of bosentan and RITONAVIR may increase steady-state bosentan maximum  
concentrations (Cmax) and area-under-the-curve (AUC). Refer to the bosentan package insert for prescribing  
information.  
Bupropion: Bupropion is primarily metabolised by CYP2B6. Concurrent administration of bupropion with  
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repeated doses of RITONAVIR is expected to decrease bupropion levels.  
Buspirone: Buspirone is primarily metabolised by CYP3A4. Concurrent administration of buspirone and  
RITONAVIR is expected to substantially elevate buspirone levels.  
Clarithromycin: the concomitant administration of NORVIR 200 mg every eight hours and clarithromycin 500  
mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax  
increased by 31 %, Cmin increased by 182 % and AUC increased by 77 % with essentially complete inhibition of  
the formation of 14-[R] hydroxy-clarithromycin. No dosage reduction should be necessary in patients with normal  
renal function. For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50 %. For  
patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75 %. Doses of clarithromycin  
greater than 1 gram per day should not be co-administered with RITONAVIR.  
Delavirdine: Delavirdine is an inhibitor of CYP3A-mediated metabolism. In a published study, concurrent  
administration of clinical doses of delavirdine 400 mg three times daily with RITONAVIR 600 mg twice daily  
(n=12 HIV-infected patients) was reported to increase steady-state ritonavir Cmax AUC by approximately 50 %  
and Cmin by about 75 %. Based on comparison to historical data, the pharmacokinetics of delavirdine did not  
appear to be affected by RITONAVIR. When used in combination with delavirdine, a dose reduction of  
RITONAVIR should be considered.  
Desipramine: Co-administration of RITONAVIR with desipramine resulted in a 145 % mean increase in the AUC  
of desipramine. Dosage reduction of desipramine should be considered in patients taking the combination.  
Didanosine: A pharmacokinetic study demonstrated that the concomitant administration of RITONAVIR 600 mg  
every 12 hours and didanosine (ddl) 200 mg every 12 hours resulted in a reduction of the ddl steady-state Cmax  
and AUC of 16 % and 13 %, respectively. In contrast, little if any effect was noted in RITONAVIR  
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pharmacokinetics. Dose alteration of ddl during concomitant RITONAVIR therapy should not be necessary;  
however, dosing of the two medicines should be separated by 2.5 hours to avoid formulation incompatibility.  
Digoxin: A literature report has shown that coadministration of NORVIR (300 mg every 12 hours) and digoxin  
resulted in significantly increased digoxin levels. Caution should be exercised when coadministration  
RITONAVIR with digoxin, with appropriate monitoring of serum digoxin levels.  
Disulfiram/Metronidazole: RITONAVIR solution and soft gelatine capsules contain ethanol (43 % and 12 %  
respectively), therefore, concomitant administration of RITONAVIR and disulfiram or medicines with disulfiram-  
like reactions (e.g.metronidazole) should be avoided.  
Efavirenz: In healthy volunteers receiving 500 mg RITONAVIR twice daily with efavirenz 600 mg once daily, the  
steady state AUC of efavirenz was increased by 21 %. An associated increase in the AUC of NORVIR of 17 %  
was observed.  
Fluticasone propionate: Concomitant use of RITONAVIR and fluticasone propionate may increase  
concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate,  
particularly for long-term use (see section 4.4).  
Fusidic acid: Co-administration of RITONAVIR with fusidic acid is expected to significantly increase fusidic acid  
and ritonavir concentrations in plasma.  
Hypericum perforatum (St. John’s Wort): Patients on RITONAVIR should not concomitantly use products  
containing St. John’s Wort (Hypericum perforatum) since it may be expected to result in reduced plasma  
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concentrations of ritonavir. This effect may be due to induction of CYP3A4 and may result in the loss of  
therapeutic effect and development of resistance (see section 4.3 and 4.4).  
Indinavir: RITONAVIR inhibits the CYP3A-mediated metabolism of indinavir. In healthy patients, 200 to 400 mg  
of RITONAVIR twice daily given with a single 400 mg to 600 mg indinavir dose increased the indinavir AUC by  
185 to 475 %, Cmax 21 % to 110 % and Cmin 11 to 33-fold, relative to 400 and 600 mg indinavir given alone.  
Concomitant administration of 400 mg RITONAVIR and 400 mg of indinavir twice daily with a meal yielded a  
similar indinavir AUC, a 4-fold increase in Cmin and a 50 to 60 % decrease in Cmax as compared to those resulting  
from administration of indinavir 800 mg three times daily under fasting conditions. Co-administration of  
RITONAVIR with indinavir will result in increased indinavir serum concentrations. There is limited safety or  
efficacy data available on the use of this  
combination in patients. The risk of nephrolithiasis may be increased when doses of indinavir equal to or greater  
than 800 mg twice daily are given with RITONAVIR. Adequate hydration and monitoring of the patients is  
warranted.  
Ketoconazole: Concomitant administration of RITONAVIR (500 mg q12h) and ketoconazole (200 mg q6h)  
resulted in an increase of mean ketoconazole AUC24 and Cmax by 244 % and 55 %, respectively. The mean half-  
life of ketoconazole increased from 2.7 to 13.2 h. Mean AUC24 and Cmax of ritonavir increased by 18 and 10 %  
respectivley. No dosage adjustment of RITONAVIR is necessary; however, doses of ketoconazole 200 mg/day  
or greater should be used with caution in combination with RITONAVIR and a decreased dosage may be  
considered.  
Methadone: Coadministration of RITONAVIR with methadone is expected to decrease methadone  
concentrations. A dosage increase of methadone may be considered.  
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Nelfinavir: Interactions between RITONAVIR and nelfinavir are likely to involve both cytochrome P450 inhibition  
and induction. Concurrent RITONAVIR 400 mg twice daily significantly increases the concentrations of M8 (the  
major active metabolite of nelfinavir) and results in a smaller increase in nelfinavir concentrations. In a study in  
ten patients nelfinavir 750 mg and RITONAVIR 400 mg twice daily yielded slightly higher nelfinavir AUC (160 %),  
Cmax (121 %) and Ctrough (123 %) than historical data for nelfinavir 750 mg three times daily monotherapy. The  
AUC of M8 was increased by 347 %.  
Oral contraceptive, patch contraceptive or implants: A pharmacokinetic study demonstrated that the  
concomitant administration of RITONAVIR 500 mg every 12 hours and a fixed-combination oral contraceptive  
resulted in reductions of the ethinyl estradiol mean Cmax and mean AUC by 32 % and 40 %, respectively.  
Increased doses of oral contraceptives or patch contraceptives containing ethinyl estradiol, or alternate methods  
of contraception, should be considered.  
Rifabutin: A pharmacokinetic study demonstrated that the concomitant administration of RITONAVIR 500 mg  
every 12 hours and rifabutin resulted in an approximate 4-fold and 35-fold increase in the AUC of rifabutin and its  
active metabolite 25-O-deacetyl rifabutin, respectively. The significance of this interaction has been confirmed in  
clinical trials. Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg/day is  
recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be  
necessary.  
Saquinavir: A pharmacokinetic study demonstrated that RITONAVIR extensively inhibits the metabolism of  
saquinavir resulting in greatly increased saquinavir plasma concentrations. Following approximately four weeks  
of a combination regimen of saquinavir (400 or 600 mg twice a day) and RITONAVIR (400 or 600 mg twice a  
day) in HIV-infected patients, saquinavir AUC values were at least 17-fold greater than historical AUC values  
from patients who received saquinavir 600 mg three times a day without RITONAVIR. When used in combination  
therapy for up to 24 weeks, doses greater than 400 mg twice a day of either RITONAVIR or saquinavir were  
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associated with an increase in adverse events.  
Sildenafil, Tadalafil & Vardenafil: Caution should be used when prescribing sildenafil, tadalafil or vardenafil for  
the treatment of erectile dysfunction in patients receiving RITONAVIR. Co-administration of NORVIR with these  
medicines is expected to increase their concentrations and may result in increased associated adverse events,  
such as hypotension and prolonged erection. Concomitant use of sildenafil with RITONAVIR is contraindicated in  
pulmonary arterial hypertension patients (see section 4.3).  
Sulfamethoxazole/trimethoprim: A pharmacokinetic study demonstrated that the concomitant administration of  
RITONAVIR 500 mg every 12 hours and sulfamethoxazole/trimethoprim resulted in a 20 % reduction of the  
sulfamethoxazole AUC and  
a
20  
%
increase of the trimethoprim AUC. Dose alteration of  
sulfamethoxazole/trimethoprim during concomitant ritonavir therapy should not be necessary.  
Theophylline: A pharmacokinetic study demonstrated that the concomitant administration of RITONAVIR 500  
mg every 12 hours and theophylline resulted in a 43 % decrease in the AUC of theophylline. An increased  
dosage of theophylline may be required.  
Tobacco: Tobacco use is associated with an 18 % decrease in the AUC of RITONAVIR.  
Trazodone: Concomitant use of RITONAVIR and trazodone may increase concentrations of trazodone. Adverse  
events of nausea, dizziness, hypotension and syncope have been observed. If trazodone is used with a CYP3A4  
inhibitor such as RITONAVIR, the combination should be used with caution and a lower dose of trazodone  
should be considered.  
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Vincristine, Vinblastine: Serum concentrations may be increased when coadministered with RITONAVIR  
resulting in the potential for increased incidence of adverse events.  
Voriconazole: A study has shown that co-administration of RITONAVIR 400 mg every 12 hours decreased  
voriconazole steady-state AUC by an average of 82 %; therefore, co-administration of these medicines are  
contraindicated (see section 4.3).  
Warfarin: Anticoagulant metabolism may be induced, resulting in decreased concentrations of warfarin.  
Zidovudine: A pharmacokinetic study demonstrated that the concomitant administration of RITONAVIR 300 mg  
every 6 hours and zidovudine (AZT) 200 mg every 8 hours resulted in a reduction of the zidovudine Cmax and  
AUC of 27 % and 25 %, respectively. In contrast, little if any effect was noted on RITONAVIR pharmacokinetics.  
Dose alteration of AZT during concomitant ritonavir therapy should not be necessary.  
Table 3:  
Effect on AUC and Cmax of Co-administration of RITONAVIR with Other Medicines  
Medicine  
Effects on  
n
AUC % (95  
Cl)  
Cmax % (95 CI)  
Ritonavir  
Ritonavir Dosage  
Clarithromycin  
500 mg every  
12 hours 4  
days  
200 mg every 8  
hours 4 days  
22  
↑ 12 %  
↑ 15 % (2,28 %)  
(2,23 %)  
Didanosine  
200 mg every  
12 hours 4  
600 mg every 12  
hours 4 days  
12  
↔
↔
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days  
Fluconazole  
200 mg every 6  
hours 4 days  
8
↑ 12 %  
↑ 15 % (7,22 %)  
400 mg day 1,  
200 mg daily 4  
days  
(5,20 %)  
Fluoxetine 30  
mg every 12  
hours 8 days  
600 mg single  
dose  
16  
↑ 19 %  
↔
(7,34 %)  
Rifampicin 600  
mg or 300 mg  
daily 10 days1  
500 mg every 12  
hours 20 days  
7,9*  
10  
↓ -35 %  
↓ -25 % (-5,46 %)  
(7,55 %)  
Zidovudine 200 300 mg every 6  
↔
↔
mg every 8  
hours 4 days  
hours 4 days  
1 Preliminary date  
↑ Indicates increase  
↓ Indicates decrease  
↔ Indicates no change  
4.6 Fertility, pregnancy and lactation  
Pregnancy  
RONIVID is contraindicated in pregnancy and lactation as safety and efficacy have not been demonstrated.  
Animal studies do not indicate direct harmful effects of darunavir with respect to pregnancy, embryonal/foetal  
development, parturition or postnatal development.  
Studies with ritonavir indicate no increase in the rate of birth defects compared to rates observed in population-  
based birth defect surveillance systems. Animal data have shown reproductive toxicity.  
Breastfeeding  
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It is not known whether darunavir is excreted in human milk. Studies in rats have Demonstrated that darunavir is  
excreted in milk. Because of the potential for serious adverse events in nursing infants, mothers should be  
instructed not to breastfeed if they are receiving RONIVID.  
Carcinogenesis and Mutagenesis  
Long-term carcinogenicity studies of RITONAVIR in animal systems have not been completed. RITONAVIR was  
not found to be mutagenic or clastogenic.  
4.7 Effects on ability to drive and use machines  
No studies on the effects of RONIVID on the ability to drive or use machines have been performed. However,  
somnolence and dizziness have been reported in some patients during treatment with regimens containing  
darunavir and ritonavir, and should be borne in mind when considering a patient’s ability to drive or operate  
machinery.  
4.8 Undesirable Effects  
Summary of the safety profile  
RITONAVIR  
The most frequent reported clinical adverse events, other than asthenia, among patients receiving ritonavir were  
gastrointestinal and neurological disturbances including nausea, diarrhoea, vomiting, anorexia, abdominal pain,  
taste perversion and circumoral and peripheral paraesthesias.  
Tabulated summary of adverse reactions  
Darunavir  
SYSTEM ORGAN CLASS  
Immune system disorders  
FREQUENCY  
Less frequent  
Frequent  
ADVERSE REACTION  
Immune reconstitution syndrome  
Metabolism and nutrition  
disorders  
Hypercholesterolaemia, hyperglycaemia  
hyperlipaemia, hypertriglyceridaemia  
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Less frequent  
Diabetes mellitus, anorexia, dyslipidaemia,  
lipodystrophy, low density lipoprotein  
increased  
Psychiatric disorders  
Less frequent  
Frequent  
Abnormal dreams  
Headache  
Nervous system disorders  
Gastrointestinal disorders  
Less frequent  
Diarrhoea, vomiting, nausea, abdominal  
pain, abdominal distension, dyspepsia,  
flatulence, pancreatic enzymes increased,  
acute pancreatitis  
Hepato-biliary disorders  
Less frequent  
Frequent  
Hepatitis acute  
Rash  
Skin and subcutaneous  
tissue disorders  
Less frequent  
Pruritus, angioedema, Stevens-Johnson  
Syndrome  
Musculoskeletal and  
connective tissue  
disorders  
Less frequent  
Myalgia  
Reproductive system and  
breast disorders  
Less frequent  
Less frequent  
Gynaecomastia  
Asthenia, fatigue  
General disorders and  
administration site  
conditions  
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RITONAVIR  
SYSTEM ORGAN CLASS  
FREQUENCY  
ADVERSE REACTION  
Infections and Infestations Frequent  
Pharyngitis  
Blood and lymphatic  
system disorders  
Less frequent  
Anaemia, ecchymosis, leukopenia,  
lymphadenopathy, lymphocytosis,  
thrombocytopenia  
Immune system disorders  
Endocrine disorders  
Frequent  
Allergic reaction  
Diabetes mellitus  
Less frequent  
Frequent  
Metabolism and nutrition  
disorders  
Anorexia, hyperlipaemia, weight loss,  
avitaminosis, cachexia, dehydration,  
oedema, glycosuria, gout,  
hypercholesterolaemia, peripheral  
oedema, redistribution/ accumulation of  
body fat (see section 4.4)  
Psychiatric disorders  
Frequent  
Anxiety, insomnia, agitation, confusion,  
depression, emotional lability, euphoria,  
hallucinations, decreased libido,  
nervousness, personality disorder,  
abnormal thinking  
Nervous system disorders  
Frequent  
Circumoral paraesthesia, headache,  
peripheral pareasthesia, taste perversion,  
dizziness, hyperaesthaesia, paraesthesia,  
somnolence  
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Less frequent  
Abnormal dreams, amnesia, aphasia,  
ataxia, convulsion, grand mal convulsion,  
inco-ordination, neuralgia, neuropathy,  
paralysis, parosmia, peripheral  
neuropathy, peripheral sensory  
neuropathy, taste loss, tremor, visual field  
defect  
Eye disorders  
Frequent  
Abnormal vision, amblyopia/blurred vision,  
blepharitis, diplopia, eye pain, iritis,  
photophobia, uveitis  
Ear and labyrinth  
disorders  
Less frequent  
Ear pain, hearing impairment, increased  
cerumen, tinnitus, vertigo  
Cardiac disorders  
Vascular disorders  
Less frequent  
Frequent  
Palpitations, snycope  
Haemorrhage, hypotension, migraine,  
peripheral vascular disorder, postural  
hypotention, tachycardia  
Respiratory, thoracic and  
mediastinal disorders  
Frequent  
Increased cough  
Less frequent  
Asthma, dyspnoea, epistaxis, hiccup,  
hypoventilation, interstitial pneumonia,  
lung disorder and rhinitis, dry mouth,  
dyspepsia, eructation, flatulence, local  
throat irritation, mouth ulcer  
Gastrointestinal disorders  
Frequent  
Abdominal pain, diarrhoea, nausea,  
vomiting  
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Less frequent  
Abdomen enlarged, abnormal stools,  
bloody diarrhoea cheilitis, colitis,  
constipation, dysphagia, oesophagitis,  
gastritis, gastroenteritis, gastrointestinal  
disorder, gastrointestinal haemorrhage,  
gingivitis, ileitis, oral moniliasis,  
pancreatitis, periodontal abscess, rectal  
disorder, tenesmus, thirst  
Hepato-biliary disorders  
Frequent  
Frequent  
Cholangitis, hepatitis, hepatomegaly, liver  
damage  
Skin and subcutaneous  
tissue disorders  
Macropapular rash, pruritus, rash,  
sweating, acne, contact dermatitis, dry  
skin, eczema, facial oedema, folliculitis,  
molluscum contagiosum, photosensitivity  
reaction, psoriasis, seborrhoea, urticaria,  
vesiculobullous rash  
Musculoskeletal and  
connective tissue  
disorders  
Frequent  
Myalgia, arthalgia,arthrosis, back pain,  
facial pain, joint disorder, muscle cramps,  
muscle weakness,myositis, neck pain,  
neck rigidity, twitching  
Renal and urinary  
disorders  
Frequent  
Dysuria, haematuria, kidney calculus,  
kidney failure kidney pain, nocturia,  
polyuria, pyelonephritis, urethritis, urinary  
frequency, urinary retention  
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Reproductive system and  
breast disorders  
Less frequent  
Impotence, penis disorder  
Asthenia, fever, pain,  
General disorders and  
administration site  
conditions  
Frequent  
Less frequent  
Abnormal gait, chest pain, chills, flu  
syndrome, malaise, substernal chest pain  
Investigations  
Frequent  
Abnormal liver function tests  
Less frequent  
Abnormal electro-oculogram, abnormal  
electroretinogram, altered hormone level  
Injury and poisoning  
Less frequent  
Frequent  
Accidental injury, hypothermia  
Vasodilation  
Surgical and medical  
procedures  
POST-MARKETING EXPERIENCE  
Darunavir  
Adverse drug reactions identified during post-marketing experience.  
System Organ Class  
Adverse Drug Reaction  
Immune system disorders  
Hypersensitivity  
Skin and subcutaneous tissue disorders  
Toxic epidermal necrolysis, acute generalised  
exanthematous pustulosis  
Musculoskeletal and connective tissue  
disorders  
Osteonecrosis  
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV  
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patients, including 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 also been associated with metabolic abnormalities such as  
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.  
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral  
therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease  
inhibitors, particularly in combination with NRTIs.  
Patients co-infected with hepatitis B and/or hepatitis C virus  
In patients co-infected with hepatitis B or C virus receiving RONIVID, the incidence of adverse events and clinical  
chemistry abnormalities were not higher than in patients receiving RONIVID who were not co-infected, except for  
increased hepatic enzymes (see section 4.4). The pharmacokinetic exposure in co-infected patients was  
comparable to that in patients without co-infection.  
RITONAVIR  
Nervous system disorders: There have been post-marketing reports of seizure. Cause and effect relationship  
has not been established.  
Metabolism and nutrition disorders: Dehydration, usually associated with gastrointestinal symptoms, and  
sometimes resulting in hypotension, syncope or renal insufficiency has been reported. Syncope, orthostatic  
hypotension and renal insufficiency have also been reported without known dehydration.  
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Cardiac disorders: Myocardial infarction has been reported.  
Reproductive system and breast disorders: Menorrhagia has been reported.  
Reporting suspected adverse reactions after authorisation of RONIVID is important. It allows continued  
monitoring of the benefit/risk balance of the RONIVID. Healthcare professionals are asked to report any  
suspected adverse to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug  
Reactions  
Reporting  
Form”,  
found  
online  
under  
SAHPRA’s  
publications:  
https://www.sahpra.org.za/publications/Index/8 or to the Holder of certificate of registration through the mail:  
pvg.cdma@heterogroups.com  
4.9 Overdose  
Human experience of acute overdose with RONIVID is limited.  
Management of Overdosage:  
There is no specific antidote for overdose with RONIVID. Treatment of overdose  
with RONIVID should consist of general supportive measures including monitoring of vital signs and observation  
of the clinical status of the patient. It is proposed that management of overdose could also entail and  
administration of activated charcoal. Since RONIVID is extensively metabolised by the liver and is highly protein  
bound, dialysis is unlikely to be beneficial in significant removal of the medicine.  
5 PHARMACOLOGICAL PROPERTIES  
CATERGORY AND CLASS: A.20.2.8 Antiviral agents.  
Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitors, ATC code:  
J05AE10.  
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5.1 Pharmacodynamic properties  
Darunavir  
Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol  
polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles.  
Darunavir tightly binds to the HIV-1 protease.  
Antiviral activity in vitro  
Darunavir exhibited activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-  
2
in  
acutely  
infected  
T-cell  
lines,  
human  
peripheral  
blood  
mononuclear  
cells  
and  
human  
monocytes/macrophages in vitro with median EC50 values ranging from 1,2 to 8,5 nM (0,7 to 5,0 ng/mL).  
The EC50 value of darunavir increases by a median factor of 5,4 in the presence of human serum. Darunavir  
showed synergistic antiviral activity when studied in combination with the protease inhibitors ritonavir, nelfinavir,  
or amprenavir and additive antiviral activity when studied in combination with the protease inhibitors indinavir,  
saquinavir, lopinavir, atazanavir, or tipranavir, the N(t)RTIs zidovudine, lamivudine, zalcitabine, didanosine,  
stavudine, abacavir, emtricitabine, or tenofovir, the NNRTIs etravirine, nevirapine, delavirdine, or efavirenz and  
the fusion inhibitor enfuvirtide. No antagonism was observed between darunavir and any of those antiretrovirals.  
Resistance in vitro  
In vitro darunavir-resistant virus isolates from wildtype HIV-1 selected viruses showing decreased susceptibility  
to darunavir (range: 6-21-fold) harboured 3 to 6 amino acid substitutions in the protease gene. Determinants of  
decreased susceptibility to darunavir in  
those viruses have not been identified.  
In vitro selection of darunavir resistant HIV-1 (range: 53 641 fold change in EC50 values) from 9 HIV-1 strains  
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harbouring multiple PI (protease inhibitor) resistance-associated mutations (RAMs) resulted in the overall  
emergence of 22 mutations in the protease, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V  
and I84V were present in more than 50 % of the 9 darunavir resistant isolates. A minimum of 8 of these  
darunavir in vitro selected mutations, from which at least 2 were already present in the protease prior to  
selection, were required in the HIV- 1 protease to render a virus resistant (fold change [FC] > 10) to darunavir.  
In 1 113 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir  
and/or tipranavir and in 886 baseline isolates from the patients enrolled in clinical trials, only the subgroups with  
> 10 PI RAMs showed a median FC for darunavir > 10.  
Cross-resistance in vitro  
Cross-resistance has been observed among HIV protease inhibitors. Darunavir has a < 10-  
fold decreased susceptibility against 90 % of 3 309 clinical isolates resistant to at least one protease inhibitor.  
Seven of the nine darunavir resistant viruses selected from PI resistant viruses had phenotypic data for  
tipranavir. Six of those showed a fold change (FC) < 3 for tipranavir, indicative of cross-resistance between these  
2 protease inhibitors.  
Cross-resistance between darunavir and the nucleoside/nucleotide reverse transcriptase inhibitors, the non-  
nucleoside reverse transcriptase inhibitors, the entry inhibitors or the integrase inhibitors, is unlikely because the  
viral targets for those inhibitors are different.  
RITONAVIR  
Ritonavir is a peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases. Inhibition of HIV protease  
renders the enzyme incapable of processing the gag-pol polyprotein precursor and leads to the production of HIV  
particles with immature morphology that are unable to initiate new rounds of infection. Ritonavir has selective  
affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.  
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Ritonavir is used in this combination as pharmacokinetic enhancer, as it is an inhibitor of CYP3A, thereby  
increasing the plasma concentrations of darunavir.  
In vitro data indicate that ritonavir is active against all strains of HIV tested in a variety of transformed and  
primary human cell lines. The concentration of ritonavir that inhibits 50 % and 90 % of viral replication in vitro in  
plasma-free surroundings is approximately 0,02 μm and 0,11 μm, respectively. Similar potencies were found with  
both AZT-sensitive and AZT-resistant strains of HIV. Studies which measured direct cell toxicity of ritonavir on  
several cell lines, showed no direct toxicity at concentrations up to 25 μm, with a resulting in vitro therapeutic  
index of at least 1000.  
Ritonavir-resistant isolates of HIV-1 have been selected in vitro. The resistant isolates showed reduced  
susceptibility to ritonavir and genotypic analysis showed that the resistance was attributable primarily to specific  
amino acid substitutions in the HIV-1 protease at codons V82F, I84V, A71V and M46I. Phenotypic and genotypic  
changes in HIV isolates from selected patients treated with ritonavir were monitored in Phase I/II trials. Serial  
genotypic and phenotypic analysis indicated that susceptibility to ritonavir declined in an ordered and stepwise  
fashion. Initial mutations occurred at positions 82 (Val to Ala/Phe), 54 (Ile to Val), 71 (Ala to Val/Thr) and 36 (Ile  
to Leu), followed by combinations of mutations at an additional 5 specifc amino acid positions. Viral strains  
isolated in vivo without a change at codon 82 did not have decreased susceptibility to ritonavir. The 82 mutation  
appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined  
as a greater than or equal to five-fold decrease in viral sensitivity in vitro from baseline. The clinical relevance of  
phenotypic and genotypic changes associated with ritonavir therapy has not been established.  
The potential for HIV cross-resistance between protease inhibitors has not been fully explored. Therefore, it is  
unknown what effect ritonavir therapy will have on the activity of concordantly or subsequently administered  
protease inhibitors. Serial HIV isolates obtained from six patients during ritonavir therapy showed a decrease in  
ritonavir susceptibility in vitro but did not demonstrate a concordant decrease in susceptibility to saquinavir in  
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vitro when compared to matched baseline isolates. However, isolates from two of these patients demonstrated  
decreased susceptibility to indinavir in vitro (8-fold). Isolates from five patients were also tested for cross  
resistance to amprenavir and nelfinavir; isolates from two patients had a decrease in susceptibility to nelfinavir  
(12 to 14-fold), and none to amprenavir. Cross- resistance between ritonavir and reverse transcriptase inhibitors  
is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV isolate tested in vitro  
retained full susceptibility to ritonavir.  
5.2 Pharmacokinetic Properties  
The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult  
volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in  
healthy patients. The increased exposure to darunavir in HIV-1 infected patients compared to healthy patients  
may be explained by the  
higher concentrations of alpha-1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir  
binding to plasma AAG and, therefore, higher plasma concentrations. Darunavir is primarily metabolised by  
CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.  
Absorption  
Darunavir was well absorbed following oral administration in the presence of low-dose ritonavir. Maximum  
plasma concentration of darunavir in the presence of low-dose ritonavir is generally achieved within 2,5 to 4,0  
hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37 % and  
increased to approximately 82 % in the presence of 100 mg twice daily ritonavir. The overall pharmacokinetic  
enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir  
when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily (see  
section 4.4). When administered without food, the relative bioavailability of darunavir in the presence of low dose  
ritonavir is 30 % lower as compared to intake with food. Therefore, darunavir tablets should be taken with  
ritonavir and with food. The type of food does not affect exposure to darunavir.  
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Distribution  
Darunavir is approximately 95 % bound to plasma protein. Darunavir binds primarily to plasma alpha-1-acid  
glycoprotein.  
Metabolism  
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative  
metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme  
CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a  
single 400/100 mg darunavir/rtv dose was due to the parent substance. At least 3 oxidative metabolites of  
darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of  
darunavir against wild type HIV.  
Elimination  
After a 400/100 mg 14C -darunavir/rtv dose, approximately 79,5 % and 13,9 % of the administered dose of 14C -  
darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately  
41,2 % and 7,7 % of the administered dose in faeces and urine, respectively. The terminal elimination half-life of  
darunavir was approximately 15 hours when combined with ritonavir. The intravenous clearance of darunavir  
alone (150 mg) and in the presence of low-dose ritonavir was 32,8 l/h and 5,9 l/h, respectively.  
Special populations  
Paediatrics  
There is no information on the use of darunavir in combination with ritonavir in the paediatric population for the  
once daily dose.  
Elderly  
Population pharmacokinetic analysis in HIV-infected patients showed that darunavir pharmacokinetics are not  
considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (see section 4.4).  
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Gender  
Population pharmacokinetic analysis showed a slightly higher darunavir exposure in HIV infected females  
compared to males. This difference is not clinically relevant.  
Renal impairment  
Results from a mass balance study with 14C-darunavir/rtv showed that approximately 7,7 % of the administered  
dose of darunavir is excreted in the urine as unchanged substance. Darunavir has not been studied in patients  
with renal impairment.  
Hepatic impairment  
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with  
darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the steady-state  
pharmacokinetic parameters of darunavir in subjects with mild (Child-Pugh Class A,) and moderate (Child Pugh  
Class B) hepatic impairment were comparable with those in healthy patients. The effect of severe hepatic  
impairment on the pharmacokinetics of darunavir has not been studied (see section 4.2 and 4.4).  
Ritonavir:  
In a pharmacokinetic study in HIV positive fasting subjects, high levels of ritonavir were achieved and maintained  
for several hours after oral administration of 100 mg, 200 mg, 400 mg, 600 mg, 800 mg or 1 000 mg or ritonavir.  
Area under the concentration-time curve (AUC) ranged from 3,92 to 123 μg,h/mL, respectively and the maximal  
concentration (Cmax) ranged from 0,416 to 12,7 μg/mL. The pharmacokinetics of ritonavir was dose-dependent;  
with more than proportional increases in the AUC and Cmax occurring with increasing dose. The time to  
maximum concentration (Tmax) remained constant at approximately 2- 4 hours with increasing dose. Renal  
clearance averaged less than 0,1ℓ/h and was relatively constant throughout the dosage range. There is no  
parenteral formulation of ritonavir, therefore, the absolute bioavailability has not been determined.  
After administration of a single 100 mg dose tablet, the area under concentration-time curve (AUC) is 3,7  
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μg.h/mL, maximal concentration (Cmax) is 0,44 ± 0,29 μg/mL, Tmax is 4,4 ± 1,2 h.  
Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was  
12 % higher when administered with high fat meal. When the liquid formulation was given under fasting  
conditions, peak ritonavir concentrations increased 28 %, relative to non-fasting conditions. The clinical  
implications of these differences are not known.  
The pharmacokinetics of ritonavir during multiple dose regimens were studied in non-fasting HIV positive adult  
volunteers. Upon multiple dosing, ritonavir accumulation is less than predicted from single dose due to a time  
and dose related increase in apparent clearance (CI/F). Trough concentrations of ritonavir were observed to  
decrease over time, possibly due to enzyme induction, but appeared to stabilise by the end of 2 weeks. At steady  
state with a 600 mg twice day dose, Cmax and Ctrough values of 141,2 and 3,7 μg/mL were observed,  
respectively.  
The t½ of ritonavir was approximately 3 to 5 hours. The steady-state apparent clearance in patients treated with  
6600 mg twice a day has averaged 8,8 ± 3,2 L/h.  
No clinically significant differences in AUC or Cmax were noted between males and females. Ritonavir  
pharmacokinetic parameters were not significantly associated with body weight or lean body mass. The  
apparent volume if distribution (VD/F) of ritonavir is approximately 0,41 ± 0,25 L/kg after a single dose. The  
protein binding of ritonavir in human plasma was noted to be approximately 98 to 99 %. Ritonavir binds to both  
human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities. Total  
plasma protein binding is constant over the concentration range 1 to 100 μ/mL.  
Tissue distribution studies with 14C-labelled ritonavir in rats showed the liver, adrenals, pancreas, kidneys and  
thyroid to have the highest concentrations of ritonavir. Tissue to plasma ratios of approximately one measured in  
rat lymph nodes suggests that ritonavir distributes into lymphatic tissue. Ritonavir penetrates minimally into the  
brain.  
Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily isozyme  
CYP3A and to a lesser extent CYP2D6. Animal studies as well as in vitro experiments with human hepatic  
microsomes indicated that ritonavir primarily underwent oxidative metabolism. Five ritonavir metabolites have  
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been identified in man. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral  
activity similar to that of ritonavir. However, the AUC of the M-2 metabolite was approximately 3 % of the AUC of  
ritonavir.  
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the  
hepatobiliary system; approximately 86 % of radiolabel was recovered in the stool. In these studies, renal  
elimination was not found to be major route of elimination of ritonavir.  
Effects on electrocardiogram:  
QTcF interval was evaluated in placebo and active (moxifloxacin 400 mg once daily) controlled crossover study  
in healthy adults, with measurements over 12 hours on Day 3. The maximum mean (95 % upper confidence  
bound) difference in QTcF from placebo was 5,5 (7,6) msec for 400 mg twice daily ritonavir. The Day 3 ritonavir  
exposure was approximately 1,5-fold higher than that observed with the 600 mg twice-daily dose at steady state.  
No subject experiences an increase in QTcF of > 60 msec from baseline or a QTcF interval exceeding the  
potentially clinically relevant threshold of 500 msec. Modest prolongation of the PR interval was also noted in  
subjects receiving ritonavir in the same study on Day 3. Maximum PR interval was 252 msec and no second- or  
third-degree heart block was observed.  
Renal impairment:  
Currently there is no data specific to this patient population. However, because ritonavir is highly protein bound it  
is unlikely that ritonavir will be significantly removed by haemodialysis or peritoneal dialysis (see Section 4.2 and  
4.4).  
Hepatic impairment:  
In HIV-infected adult subjects with mild hepatic insufficiency dosed with ritonavir 400 mg twice a day, ritonavir  
exposures were similar to control subjects dosed with 500 mg twice a day. Results indicated that dose  
adjustment is not required in patients with mild hepatic impairment. Adequate pharmacokinetic data are not  
available for patients with moderate hepatic impairment. Protein binding ritonavir was not statistically significantly  
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affected by mild or moderately impaired hepatic function (see Section 4.2, 4.3 and 4.4).  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
•
•
•
Darunavir Ethanolate  
Ritonavir  
Silicifide microcrystalline cellulose  
Crosprovidone  
•
•
•
•
•
•
Colloidal silicon dioxide  
Magnesium stearate  
Copovidone  
Sorbitan monolaurate  
Dibasic calcium phosphate anhydrous  
Sodium stearyl fumarate  
Composition of Opadry yellow 16C82767  
•
•
•
•
•
•
HPMC/Hypromellose 6cP  
Titanium dioxide  
Macrogol/PEG 400  
HPMC/Hypromellose 15cP  
Hydroxypropyl cellulose  
Iron oxide yellow  
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•
•
•
•
Talc  
Macrogol/PEG 3350  
Colloidal anhydrous silica  
Polysorbate 80  
6.2. Incompatibilities  
N/A  
6.3 Shelf life  
24 months  
6.4 Special precautions for storage  
Store at or below 25 °C. Protect from light and moisture.  
Keep the tablets in the original container until required for  
KEEP OUT OF REACH OF CHILDREN.  
6.5 Nature and contents of container  
30’s count HDPE container  
High density polyethylene container 100 cc with 38 mm Neck (heavy weight) with a child resistant plastic caps  
with pulp liners 38 mm with a desiccant canister 2,0 g, silica gel  
56’s and 60’s count HDPE container  
High density polyethylene container 150 cc with 38 mm Neck (heavy weight) with a child  
resistant plastic caps with pulp liners 38 mm with a desiccant canister 2,0 g, silica gel  
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120’s count HDPE container  
High density polyethylene container 300 cc with 53 mm Neck (heavy weight) with a child  
resistant plastic caps with pulp liners 53 mm with a desiccant canister 2,0 g, silica gel  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate  
Campus, Building No.2,  
First Floor, 74 Waterfall Drive, Midrand, 2066  
Telephone number: 012 644 1220  
Fax number: 012 644 1564  
e-mail address: nokuthula.n@heterodrugs.com  
8 REGISTRATION NUMBER(S)  
RONIVID 400/50 mg: 56/20.2.8/0838  
9 DATE OF FIRST AUTHORISATION/ RENEWAL OF AUTHORISATION  
25 July 2023  
10 DATE OF REVISION OF THE TEXT  
To be allocated by the Authority upon registration.  
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