Aptivus

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Aptivus 250 mg soft capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each soft capsule contains 250 mg tipranavir. 

Excipients with known effect: Each soft capsule contains 
100.0 mg ethanol, 455.0 mg macrogolglycerol ricinoleate and 12.6 mg sorbitol

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Soft capsule.

Pink, oblong soft gelatin capsules imprinted with “TPV 250” in black.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Aptivus, co-administered with low dose ritonavir, is indicated for combination antiretroviral treatment 
of HIV-1 infection in highly pre-treated adults and adolescents 12 years of age or older with virus 
resistant to multiple protease inhibitors. Aptivus should only be used as part of an active combination 
antiretroviral regimen in patients with no other therapeutic options.

In deciding to initiate treatment with Aptivus, co-administered with low dose ritonavir, careful 
consideration should be given to the treatment history of the individual patient and the patterns of 
mutations associated with different agents. Genotypic or phenotypic testing (when available) and 
treatment history should guide the use of Aptivus. Initiation of treatment should take into account the 
combinations of mutations which may negatively impact the virological response to Aptivus, co-
administered with low dose ritonavir (see section 5.1).

4.2 Posology and method of administration

Aptivus must always be given with low dose ritonavir as a pharmacokinetic enhancer, and in 
combination with other antiretroviral medicinal products. The Summary of Product Characteristics of 
ritonavir must therefore be consulted prior to initiation of therapy with Aptivus (especially as regards 
the contraindications, warnings and undesirable effects sections).

Aptivus should be prescribed by physicians who are experienced in the treatment of HIV-1 infection. 

Posology
Adults and adolescents (from 12 – 18 years of age)
The recommended dose of Aptivus is 500 mg, co-administered with 200 mg ritonavir (low dose 
ritonavir), twice daily (see section 4.4 for precautionary measures in adolescents).

Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy 
profile of the combination.
Since currently only limited efficacy and safety data are available for adolescents (see section 5.1) 
close monitoring of virologic response and tolerance is particularly warranted in this patient group.



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Missed dose
Patients should be advised of the need to take Aptivus and ritonavir every day as prescribed. If a dose 
is missed by more than 5 hours, the patient should be instructed to wait and then to take the next dose 
of Aptivus and ritonavir at the regularly scheduled time. If a dose is missed by less than 5 hours, the 
patient should be instructed to take the missed dose immediately, and then to take the next dose of 
Aptivus and ritonavir at the regularly scheduled time.

Elderly
Clinical studies of Aptivus did not include sufficient numbers of subjects aged 65 and over to 
determine whether they respond differently from younger subjects (see section 5.2).
In general, caution should be exercised in the administration and monitoring of Aptivus in older 
people reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of 
concomitant disease or other therapy (see section 4.4).

Liver impairment
Tipranavir is metabolised by the hepatic system. Liver impairment could therefore result in an increase 
of tipranavir exposure and a worsening of its safety profile. Therefore, Aptivus should be used with 
caution, and with increased monitoring frequency, in patients with mild hepatic impairment (Child-
Pugh Class A). Aptivus is contraindicated in patients with moderate or severe (Child-Pugh Class B or 
C) hepatic impairment (see sections 4.3, 4.4 and 5.2).

Renal impairment
No dosage adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of Aptivus capsules in children aged 2 to 12 years has not been established. 
Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology can 
be made.

Also, appropriate dose adjustments for children under 12 years cannot be achieved with Aptivus 
capsules. Aptivus oral solution is available for children between 2 and 12 years of age (please refer to 
the respective SmPC for further details).

The safety and efficacy of Aptivus in children under 2 years of age has not been established. No data 
are available. 

Method of administration 
Oral use.
Aptivus soft capsules co-administered with low dose ritonavir should be taken with food (see section 
5.2).
Aptivus soft capsules must be swallowed whole and must not be opened or chewed.

4.3 Contraindications

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

Patients with moderate or severe (Child-Pugh B or C) hepatic impairment. 

Combination of rifampicin with Aptivus with concomitant low dose ritonavir is contraindicated (see 
section 4.5).

Herbal preparations containing St John’s wort (Hypericum perforatum) due to the risk of decreased 
plasma concentrations and reduced clinical effects of tipranavir (see section 4.5).

Co-administration of Aptivus with low dose ritonavir, with active substances that are highly dependent 
on CYP3A for clearance, and for which elevated plasma concentrations are associated with serious 
and/or life-threatening events. These active substances include antiarrhythmics (such as amiodarone, 



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bepridil, quinidine), antihistamines (such as astemizole, terfenadine), ergot derivatives (such as 
dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (such 
as cisapride), antipsychotics (such as pimozide, sertindole, quetiapine, lurasidone), sedatives/hypnotics 
(such as orally administered midazolam and triazolam) and HMG-CoA reductase inhibitors (such as 
simvastatin and lovastatin) (see section 4.5). Also the use of the alpha-1 adrenoceptor antagonist 
alfuzosin, and sildenafil when used for the treatment of pulmonary arterial hypertension. In addition, 
co-administration of Aptivus with low dose ritonavir, and medicinal products that are highly 
dependent on CYP2D6 for clearance, such as the antiarrhythmics flecainide, propafenone and 
metoprolol given in heart failure (see section 4.5).

Co-administration of colchicine with Aptivus/ritonavir in patients with renal or hepatic impairment 
(see section 4.5).

4.4 Special warnings and precautions for use

Aptivus must be administered with low dose ritonavir to ensure its therapeutic effect (see section 4.2). 
Failure to correctly co-administer tipranavir with ritonavir will result in reduced plasma levels of 
tipranavir that may be insufficient to achieve the desired antiviral effect. Patients should be instructed 
accordingly. 

Aptivus is not a cure for HIV-1 infection or AIDS. Patients receiving Aptivus or any other 
antiretroviral therapy may continue to develop opportunistic infections and other complications of 
HIV-1 infection.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission 
should be taken in accordance with national guidelines. 

Switching from Aptivus capsules to the oral solution
Aptivus capsules are not interchangeable with the oral solution. Compared to the capsules, tipranavir 
exposure is higher when administering the same dose as oral solution. Also, the composition of the 
oral solution is different from that of the capsules, with the high vitamin E content being especially 
noteworthy. Both of these factors may contribute to an increased risk of adverse reactions (type, 
frequency and/or severity). Therefore patients should not be switched from Aptivus capsules to 
Aptivus oral solution (see sections 5.1 and 5.2). 

Switching from Aptivus oral solution to the capsules
Aptivus oral solution is not interchangeable with the capsules. Compared to the oral solution, 
tipranavir exposure is lower when administering the same dose as capsules. However, children 
previously treated with Aptivus oral solution and becoming 12 years of age should be switched to 
capsules, particularly because of the more favourable safety profile of the capsules. It has to be noted 
that the switch from the oral solution to the capsule formulation of Aptivus could be associated with 
decreased exposure. Therefore, it is recommended that patients switching from Aptivus oral solution 
to capsules at the age of 12 years are closely monitored for the virologic response of their 
antiretroviral regimen (see sections 5.1 and 5.2).

Liver disease
Aptivus is contraindicated in patients with moderate or severe (Child-Pugh Class B or C) hepatic 
insufficiency. Limited data are currently available for the use of Aptivus, co-administered with low 
dose ritonavir, in patients co-infected with hepatitis B or C. Patients with chronic hepatitis B or C and 
treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal 
hepatic adverse reaction. Aptivus should be used in this patient population only if the potential benefit 
outweighs the potential risk, and with increased clinical and laboratory monitoring. In the case of 
concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of 
Product Characteristics for these medicinal products.

Patients with mild hepatic impairment (Child-Pugh Class A) should be closely monitored.



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Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased 
frequency of liver function abnormalities during combination therapy and should be monitored 
according to standard practice. Aptivus with ritonavir should be discontinued once signs of worsening 
liver function occur in patients with pre-existing liver disease.

Aptivus co-administered with low dose ritonavir, has been associated with reports of clinical hepatitis 
and hepatic decompensation, including some fatalities. These have generally occurred in patients with 
advanced HIV disease taking multiple concomitant medicinal products. Caution should be exercised 
when administering Aptivus to patients with liver enzyme abnormalities or with a history of hepatitis. 
Increased ALAT/ASAT monitoring should be considered in these patients.

Aptivus therapy should not be initiated in patients with pre-treatment ASAT or ALAT greater than 5 
times the Upper Limit Normal (ULN) until baseline ASAT/ALAT is stabilised at less than 5X ULN, 
unless the potential benefit justifies the potential risk.

Aptivus therapy should be discontinued in patients experiencing ASAT or ALAT elevations greater 
than 10X ULN, or developing signs or symptoms of clinical hepatitis during therapy. If another cause 
is identified (eg acute hepatitis A, B or C virus, gallbladder disease, other medicinal products), then 
rechallenge with Aptivus may be considered when ASAT/ALAT have returned to the patient’s 
baseline levels.

Liver monitoring
Monitoring of hepatic tests should be done prior to initiation of therapy, after two, four and then every 
four weeks until 24 weeks, and then every eight to twelve weeks thereafter. Increased monitoring (i.e. 
prior to initiation of therapy, every two weeks during the first three months of treatment, then monthly 
until 48 weeks, and then every eight to twelve weeks thereafter) is warranted when Aptivus and low 
dose ritonavir are administered to patients with elevated ASAT and ALAT levels, mild hepatic 
impairment, chronic hepatitis B or C, or other underlying liver disease.

Treatment-naïve patients
In a study performed in antiretroviral naïve adult patients, tipranavir 500 mg with ritonavir 200 mg 
twice daily, as compared to lopinavir/ritonavir, was associated with an excess in the occurrence of 
significant (grade 3 and 4) transaminase elevations without any advantage in terms of efficacy (trend 
towards a lower efficacy). The study was prematurely stopped after 60 weeks.
Therefore, tipranavir with ritonavir should not be used in treatment-naïve patients (see section 4.2).

Renal impairment
Since the renal clearance of tipranavir is negligible, increased plasma concentrations are not expected 
in patients with renal impairment.

Haemophilia
There have been reports of increased bleeding, including spontaneous skin haematomas and 
haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some 
patients additional Factor VIII was given. In more than half of the reported cases, treatment with 
protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal 
relationship has been evoked, although the mechanism of action had not been elucidated. 
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. 

Bleeding
RESIST participants receiving Aptivus with ritonavir tended to have an increased risk of bleeding; at 
24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 
1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between 
treatment groups in coagulation parameters. The significance of this finding is being further 
monitored.



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Fatal and non-fatal intracranial haemorrhages (ICH) have been reported in patients receiving Aptivus, 
many of whom had other medical conditions or were receiving concomitant medicinal products that 
may have caused or contributed to these events. However, in some cases the role of Aptivus cannot be 
excluded. No pattern of abnormal haematological or coagulation parameters has been observed in 
patients in general, or preceding the development of ICH. Therefore, routine measurement of 
coagulation parameters is not currently indicated in the management of patients on Aptivus.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS 
such as those treated in the Aptivus clinical trials.

In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels 
consistent with exposures observed in patients receiving Aptivus with ritonavir.

In rats, co-administration with vitamin E increased the bleeding effects of tipranavir (see section 5.3).

Aptivus, co-administered with low dose ritonavir, should be used with caution in patients who may be 
at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving 
medicinal products known to increase the risk of bleeding such as antiplatelet agents and 
anticoagulants or who are taking supplemental vitamin E. Based on the limits of exposure available 
from observation in clinical trials, it is recommended not to co-administer to patients more than 
1,200 IU vitamin E per day.

Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. A higher increase of blood lipids were seen with tipranavir/ritonavir 
than with comparators (other protease inhibitors) in clinical trials. For monitoring of blood lipids and 
glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed 
as clinically appropriate. 

Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, 
such reactions have been observed within the first few weeks or months of initiation of CART. 
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and 
pneumocystis pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted 
when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in 
clinical studies with Aptivus, co-administered with low dose ritonavir.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment.

Rash
Mild to moderate rashes including urticarial rash, maculopapular rash, and photosensitivity have been 
reported in subjects receiving Aptivus, co-administered with low dose ritonavir. At 48-weeks in Phase 
III trials, rash of various types was observed in 15.5% males and 20.5% females receiving Aptivus co-
administered with low dose ritonavir. Additionally, in one interaction trial, in healthy female 
volunteers administered a single dose of ethinyl oestradiol followed by Aptivus co-administered with 
low dose ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, 
throat tightness, or generalized pruritus has been reported in both men and women receiving Aptivus
co-administered with low dose ritonavir. In the paediatric clinical trial, the frequency of rash (all 
grades, all causality) through 48 weeks of treatment was higher than in adult patients.



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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.

Interactions
The interaction profile of tipranavir, co-administered with low dose ritonavir, is complex. The 
mechanisms and potential mechanisms contributing to the interaction profile of tipranavir are 
described (see section 4.5).

Abacavir and zidovudine 
The concomitant use of Aptivus, co-administered with low dose ritonavir, with zidovudine or 
abacavir, results in a significant decrease in plasma concentration of these nucleoside reverse 
transcriptase inhibitors (NRTIs). Therefore, the concomitant use of zidovudine or abacavir with 
Aptivus, co-administered with low dose ritonavir, is not-recommended unless there are no other 
available NRTIs suitable for patient management (see section 4.5).

Protease inhibitors
Concomitant use of Aptivus, co-administered with low dose ritonavir, with the protease inhibitors 
amprenavir, lopinavir or saquinavir (each co-administered with low dose ritonavir) in a dual-boosted 
regimen, results in significant decreases in plasma concentrations of these protease inhibitors. A 
significant decrease in plasma concentrations of atazanavir and a marked increase of tipranavir and 
ritonavir concentrations was observed when Aptivus, associated with low dose ritonavir, was co-
administered with atazanavir (see section 4.5). No data are currently available on interactions of 
tipranavir, co-administered with low dose ritonavir, with protease inhibitors other than those listed 
above. Therefore, the co-administration of tipranavir, co-administered with low dose ritonavir, with 
protease inhibitors is not recommended.

Oral contraceptives and oestrogens 
Since levels of ethinyl oestradiol are decreased, the co-administration of Aptivus co-administered with 
low dose ritonavir is not recommended. Alternative or additional contraceptive measures are to be 
used when oestrogen based oral contraceptives are co-administered with Aptivus co-administered with 
low dose ritonavir (see section 4.5). Patients using oestrogens as hormone replacement therapy should 
be clinically monitored for signs of oestrogen deficiency. Women using oestrogens may have an 
increased risk of non serious rash.

Anticonvulsants
Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin. Aptivus may 
be less effective due to decreased tipranavir plasma concentrations in patients taking these agents 
concomitantly (see section 4.5).

Halofantrine, lumefantrine
Due to their metabolic profile and inherent risk of inducing torsades de pointes, administration of 
halofantrine and lumefantrine with Aptivus co-administered with low dose ritonavir, is not 
recommended (see section 4.5).

Disulfiram/metronidazole
Aptivus soft capsules contain alcohol (7% ethanol, ie 100 mg per capsule or up to 200 mg per dose) 
which can produce disulfiram-like reactions when co-administered with disulfiram or other medicinal 
products which produce this reaction (e.g. metronidazole).

Fluticasone
Concomitant use of tipranavir, co-administered with low dose ritonavir, and fluticasone or other 
glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of 



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treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and 
adrenal suppression (see section 4.5).

Atorvastatin
Tipranavir, co-administered with low dose ritonavir, increases the plasma concentrations of 
atorvastatin (see section 4.5). The combination is not recommended. Other HMG-CoA reductase 
inhibitors should be considered such as pravastatin, fluvastatin or rosuvastatin (see section 4.5). 
However, if atorvastatin is specifically required for patient management, it should be started with the 
lowest dose and careful monitoring is necessary.

Omeprazole and other proton pump inhibitors
The combined use of Aptivus with ritonavir with either omeprazole, esomeprazole or with other 
proton pump inhibitors is not recommended (see section 4.5).  

Colchicine 
In patients with normal renal and hepatic function, a reduction in colchicine dosage or an interruption 
of colchicine treatment is recommended in co-administration (see section 4.5).

Salmeterol
Concomitant use of salmeterol and Aptivus, co-administered with low dose ritonavir, is not 
recommended (see section 4.5).

Bosentan
Due to the marked hepatotoxicity of bosentan and the potential for increasing the liver toxicity 
associated with Aptivus, co-administered with low dose ritonavir, this combination is not 
recommended.

Warnings related to certain excipients
Aptivus contains macrogolglycerol ricinoleate which may cause stomach upset and diarrhoea.

This medicine contains 100 mg of alcohol (ethanol) in each capsule. The amount in 250 mg of this 
medicine (i.e. one capsule) is equivalent to less than 3 ml of beer, or than 1 ml of wine.
The small amount of alcohol in this medicine will not have any noticeable effects.

4.5 Interaction with other medicinal products and other forms of interaction

The interaction profile of Aptivus, co-administered with low dose ritonavir, is complex and requires 
special attention in particular in combination with other antiretroviral agents.

Interaction studies have only been performed in adults.

Metabolic profile of tipranavir
Tipranavir is a substrate, an inducer and an inhibitor of cytochrome P450 CYP3A. When co-
administered with ritonavir at the recommended dosage (see section 4.2) there is a net inhibition of 
P450 CYP3A. Co-administration of Aptivus and low dose ritonavir with agents primarily metabolised 
by CYP3A may result in changed plasma concentrations of tipranavir or the other agents, which could 
alter their therapeutic and undesirable effects (see list and details of considered agents, below). Agents 
that are contraindicated specifically due to the expected magnitude of interaction and potential for 
serious adverse reactions are detailed in this section, and listed in section 4.3.

A cocktail study was conducted in 16 healthy volunteers with twice-daily 500 mg tipranavir with 
200 mg ritonavir  capsule administration for 10 days to assess the net effect on the activity of hepatic 
CYP 1A2 (caffeine), 2C9 (warfarin), 2D6 (dextromethorphan), both intestinal/hepatic CYP 3A4 
(midazolam) and P-glycoprotein (P-gp) (digoxin). At steady state, there was a significant induction of 
CYP 1A2 and a slight induction on CYP 2C9. Potent inhibition of CYP 2D6 and both hepatic and 
intestinal CYP 3A4 activities were observed. P-gp activity is significantly inhibited after the first dose, 



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but there was a slight induction at steady state. Practical recommendations deriving from this study are 
displayed below.

Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP 
2C19 and CYP 2D6. The potential net effect of tipranavir with ritonavir on CYP 2D6 is inhibition, 
because ritonavir is also a CYP 2D6 inhibitor. The in vivo net effect of tipranavir with ritonavir on 
CYP 1A2, CYP 2C9 and CYP 2C19, indicates, through a preliminary study, an inducing potential of 
tipranavir with ritonavir on CYP1A2 and, to a lesser extent, on CYP2C9 and P-gp after several days of 
treatment. Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl 
transferases. 

In vitro studies show that tipranavir is a substrate and also an inhibitor of P-gp. 

It is difficult to predict the net effect of Aptivus co-administered with low dose ritonavir on oral
bioavailability and plasma concentrations of agents that are dual substrates of CYP3A and P-gp. The 
net effect will vary depending on the relative affinity of the co-administered substance for CYP3A and 
P-gp, and the extent of intestinal first-pass metabolism/efflux.

Co-administration of Aptivus and agents that induce CYP3A and/or P-gp may decrease tipranavir 
concentrations and reduce its therapeutic effect (see list and details of considered agents, below). Co-
administration of Aptivus and medicinal products that inhibit P-gp may increase tipranavir plasma 
concentrations.

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal 
products are listed in the table below.

Interaction table
Interactions between Aptivus and co-administered medicinal products are listed in the table below 
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, once daily as “QD”, twice daily as 
“BID”, concentration at end of dosing interval as “Cτ”).
Unless otherwise stated, studies detailed below have been performed with the recommended dosage of 
Aptivus/r (i.e. 500/200 mg BID). However, some PK interaction studies were not performed with this 
recommended dosage. Nevertheless, the results of many of these interaction studies can be 
extrapolated to the recommended dosage since the doses used (eg. TPV/r 500/100 mg, TPV/r 
750/200 mg) represented extremes of hepatic enzyme induction and inhibition and bracketed the 
recommended dosage of Aptivus/r.

Drugs by therapeutic area Interaction
Geometric mean change (%)

Recommendations concerning
co-administration

Anti-infectives
Antiretrovirals
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
Since there is no significant impact of nucleoside and nucleotide analogues on the P450 enzyme system no 
dosage adjustment of Aptivus is required when co-administered with these agents.

Abacavir 300 mg BID
(TPV/r 750/100 mg BID)

Abacavir Cmax ↓ 46%
Abacavir AUC ↓ 36%

The clinical relevance of this 
reduction has not been 
established, but may decrease the 
efficacy of abacavir.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with abacavir is not 
recommended unless there are no 
other available NRTIs suitable for 
patient management. In such cases 
no dosage adjustment of abacavir 
can be recommended (see section 
4.4).

Didanosine 200 mg BID, ≥  
60 kg (TPV/r 250/200 mg

Didanosine Cmax ↓ 43%
Didanosine AUC ↓ 33%

Dosing of enteric-coated didanosine 
and Aptivus soft capsules, co-



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BID) - 125 mg BID, < 60 kg
(TPV/r 750/100 mg BID)

Didanosine Cmax ↓ 24%
Didanosine AUC ↔  

The clinical relevance of this 
reduction in didanosine 
concentrations has not been 
established.

Mechanism unknown.

administered with low dose 
ritonavir, should be separated by at 
least 2 hours to avoid formulation 
incompatibility.

Emtricitabine
No interaction study 
performed

Potential interactions with renal 
transporters cannot be fully
excluded.

No dosage adjustment necessary in 
patients with normal renal function.
In case of concomitant 
administration of emtricitabine and 
Aptivus/ritonavir, renal function 
should be evaluated before initiating 
the co-administration.

Lamivudine 150 mg BID
(TPV/r 750/100 mg BID)

No clinically significant 
interaction is observed.

No dosage adjustment necessary.

Stavudine
40 mg BID > 60 kg
30 mg BID < 60 kg
(TPV/r 750/100 mg BID)

No clinically significant 
interaction is observed.

No dosage adjustment necessary.

Zidovudine 300 mg BID
(TPV/r 750/100 mg BID)

Zidovudine Cmax ↓ 49%
Zidovudine AUC ↓ 36%

The clinical relevance of this 
reduction has not been 
established, but may decrease the 
efficacy of zidovudine.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir with zidovudine is not 
recommended unless there are no 
other available NRTIs suitable for 
patient management. In such cases 
no dosage adjustment of zidovudine 
can be recommended (see section 
4.4). 

Tenofovir  300 mg QD 
(TPV/r 750/200 mg BID)

No clinically significant 
interaction is observed.

No dosage adjustment necessary.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg QD No clinically significant interaction 

is observed.
No dosage adjustment necessary.

Etravirine Etravirine Cmax ↓ 71%
Etravirine AUC ↓ 76%
Etravirine Cmin ↓ 82%

Concomitant use of 
Aptivus/ritonavir caused a decrease 
of etravirine exposure that could 
significantly impair the virologic 
response to etravirine. 

Co-administration of etravirine and 
Aptivus/ritonavir is not 
recommended.

Nevirapine
No interaction study 
performed

The limited data available from a 
phase IIa study in HIV-infected 
patients suggest that no significant 
interaction is expected between 
nevirapine and TPV/r. Moreover a 
study with TPV/r and another
NNRTI (efavirenz) did not show 
any clinically relevant interaction 
(see above).

No dosage adjustment necessary.



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Rilpivirine
No interaction study 
performed

Concomitant use of rilpivirine with 
some ritonavir-boosted protease 
inhibitors has demonstrated an 
increase in the plasma 
concentrations of rilpivirine.

Close monitoring for signs of 
rilpivirine toxicity and possibly also 
dose adjustment of rilpivirine is 
recommended when co-
administered with Aptivus/ritonavir.

Protease inhibitors (PIs)
According to current treatment guidelines, dual therapy with protease inhibitors is generally not 
recommended
Amprenavir/ritonavir 
600/100 mg BID

Amprenavir Cmax ↓ 39% 
Amprenavir AUC ↓ 44% 
Amprenavir Cmin ↓ 55%

The clinical relevance of this 
reduction in amprenavir 
concentrations has not been 
established.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with amprenavir/ritonavir 
is not recommended.
If the combination is nevertheless 
considered necessary, a monitoring 
of the plasma levels of amprenavir 
is strongly encouraged (see section 
4.4).

Atazanavir/ritonavir
300/100 mg QD
(TPV/r 500/100 mg BID)

Atazanavir Cmax ↓ 57% 
Atazanavir AUC ↓ 68% 
Atazanavir Cmin ↓ 81% 

Mechanism unknown.

Tipranavir Cmax  8% 
Tipranavir AUC  20% 
Tipranavir Cmin  75%

Inhibition of CYP 3A4 by 
atazanavir/ritonavir and induction 
by tipranavir/r.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with atazanavir/ritonavir 
is not recommended.
If the co-administration is 
nevertheless considered necessary, a 
close monitoring of the safety of 
tipranavir and a monitoring of 
plasma concentrations of atazanavir 
are strongly encouraged (see section 
4.4).

Lopinavir/ritonavir
400/100 mg BID

Lopinavir Cmax ↓ 47%
Lopinavir AUC ↓ 55% 
Lopinavir Cmin ↓ 70%

The clinical relevance of this 
reduction in lopinavir 
concentrations has not been 
established.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with lopinavir/ritonavir is 
not recommended.
If the combination is nevertheless 
considered necessary, a monitoring 
of the plasma levels of lopinavir is 
strongly encouraged (see section 
4.4). 

Saquinavir/ritonavir
600/100 mg QD

Saquinavir Cmax ↓ 70% 
Saquinavir AUC ↓ 76% 
Saquinavir Cmin ↓ 82% 

The clinical relevance of this 
reduction in saquinavir 
concentrations has not been 
established.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with saquinavir/ritonavir 
is not recommended.
If the combination is nevertheless 
considered necessary, a monitoring 
of the plasma levels of saquinavir is 
strongly encouraged (see section 
4.4). 

Protease inhibitors other 
than those listed above

No data are currently available on 
interactions of tipranavir, co-
administered with low dose 
ritonavir, with protease inhibitors 
other than those listed above.

Combination with Aptivus, co-
administered with low dose 
ritonavir, is not recommended (see 
section 4.4)



12

Fusion inhibitors
Enfuvirtide 
No interaction study 
performed

In studies where tipranavir co-
administered with low-dose 
ritonavir was used with or without 
enfuvirtide, it has been observed 
that the steady-state plasma 
tipranavir trough concentration of 
patients receiving enfuvirtide were 
45% higher as compared to patients 
not receiving enfuvirtide. No 
information is available for the 
parameters AUC and Cmax. 
A pharmacokinetic interaction is 
mechanistically unexpected and the 
interaction has not been confirmed 
in a controlled interaction study.

The clinical impact of the observed 
data, especially regarding the 
tipranavir with ritonavir safety 
profile, remains unknown. 
Nevertheless, the clinical data 
available from the RESIST trials did 
not suggest any significant 
alteration of the tipranavir with 
ritonavir safety profile when 
combined with enfuvirtide as 
compared to patients treated with 
tipranavir with ritonavir without 
enfuvirtide.

Integrase strand transfer inhibitors
Raltegravir 400 mg BID Raltegravir Cmax ↔

Raltegravir AUC 0-12↔
Raltegravir C12: ↓ 45%

Despite an almost half reduction of 
C12, previous clinical studies with 
this combination did not evidence 
an impaired outcome. 

The mechanism of action is thought 
to be induction of 
glucuronosyltransferase by 
tipranavir/r.

No particular dose adjustment is 
recommended when
Aptivus/ritonavir is administered
with Raltegravir 400 mg BID.
For other doses of raltegravir,
please refer to the relevant product
information for raltegravir..

Dolutegravir 50 mg QD Dolutegravir ↓
AUC ↓ 59%
Cmax ↓ 47%
Cτ ↓ 76%
(induction of UGT1A1 and
CYP3A enzymes) 

The recommended adult dose of 
dolutegravir is 50 mg twice daily 
when co-administered with
tipranavir/ritonavir. In the presence 
of integrase class resistance this
combination should be avoided (see 
dolutegravir SmPC).

Pharmacokinetic enhancer
Cobicistat and cobicistat-
containing products

When co-administered, tipranavir 
and cobicistat exposures are 
markedly lower compared to that of 
tipranavir when boosted with low 
dose ritonavir.   

Aptivus/ritonavir should not be 
administered concomitantly with 
cobicistat or cobicistat-containing 
products.

Anti-HCV agents
Boceprevir
No interaction study 
performed

In a pharmacokinetic study of 
healthy volunteers, boceprevir 
decreased the exposure of ritonavir, 
and some ritonavir-boosted protease 
inhibitors. Boceprevir exposure was 
reduced when co-administered with 
ritonavir-boosted lopinavir or 
ritonavir-boosted darunavir. These 
drug-drug interactions may reduce 
the effectiveness of HIV protease 
inhibitors and/or boceprevir when 
co-administered. 

Coadministration of boceprevir 
with Aptivus/ritonavir is not 
recommended.



13

Telaprevir
No interaction study 
performed

Telaprevir is metabolized in the 
liver by CYP3A and is a P-
glycoprotein (P-gp) substrate, but 
other enzymes may be involved in 
the metabolism. When
Aptivus/ritonavir is co-administered 
with telaprevir, a decrease or an 
increase of telaprevir exposure 
could be expected. There is a 
heterogeneous effect of telaprevir 
on ritonavir-boosted protease 
inhibitor drug plasma levels, 
depending on the protease 
inhibitors. Therefore, a 
modification of Aptivus exposure 
cannot be ruled out.

Coadministration of telaprevir with 
Aptivus/ritonavir is not 
recommended.

Antifungals
Fluconazole 200 mg QD 
(Day 1) then 100 mg QD

Fluconazole ↔

Tipranavir Cmax ↑ 32% 
Tipranavir AUC ↑ 50% 
Tipranavir Cmin ↑ 69% 

Mechanism unknown

No dosage adjustments are 
recommended. Fluconazole doses 
200 mg/day are not recommended.

Itraconazole
Ketoconazole
No interaction study 
performed

Based on theoretical considerations 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase itraconazole or 
ketoconazole concentrations.

Based on theoretical considerations, 
tipranavir or ritonavir 
concentrations might increase upon 
co-administration with itraconazole 
or ketoconazole.

Itraconazole or ketoconazole should 
be used with caution (doses 
200 mg/day are not 
recommended).

Voriconazole
No interaction study 
performed

Due to multiple CYP isoenzyme 
systems involved in voriconazole 
metabolism, it is difficult to predict 
the interaction with tipranavir, co-
administered with low-dose 
ritonavir.

Based on the known interaction of 
voriconazole with low dose 
ritonavir (see voriconazole SmPC) 
the co-administration of tipranavir/r 
and voriconazole should be 
avoided, unless an assessment of 
the benefit/risk to the patient 
justifies the use of voriconazole.

Anti-gouts
Colchicine
No interaction study 
performed

Based on theoretical considerations, 
colchicine concentrations may 
increase upon co-administration 
with tipranavir and low dose 
ritonavir, due to tipranavir/ritonavir 
CYP3A and P-gp inhibition. 
However a decrease of colchicine 
concentrations cannot be excluded 
since both tipranavir and ritonavir 
exhibit inducing potential towards 
CYP3A and P-gp.

Colchicine is a substrate of 

A reduction in colchicine dosage or 
an interruption of colchicine 
treatment is recommended in 
patients with normal renal or 
hepatic function if treatment with 
Aptivus/ritonavir is required (see 
section 4.4).
In patients with renal or hepatic 
impairment, co-administration of 
colchicine in patients on 
Aptivus/ritonavir is contraindicated
(see section 4.3).



14

CYP3A4 and P-gp (an intestinal 
efflux transporter).

Antibiotics
Clarithromycin 500 mg 
BID

Clarithromycin Cmax ↔ 
Clarithromycin AUC ↑ 19% 
Clarithromycin Cmin ↑ 68% 

14-OH-clarithromycin Cmax ↓ 97%
14-OH-clarithromycin AUC ↓ 97% 
14-OH-clarithromycin Cmin ↓ 95% 

Tipranavir Cmax ↑ 40%
Tipranavir AUC ↑ 66% 
Tipranavir Cmin ↑ 100%

CYP 3A4 inhibition by tipranavir/r 
and P-gp (an intestinal efflux 
transporter) inhibition by 
clarithromycin.

Whilst the changes in 
clarithromycin parameters are not 
considered clinically relevant, the 
reduction in the 14-OH metabolite 
AUC should be considered for the 
treatment of infections caused by 
Haemophilus influenzae in which 
the 14-OH metabolite is most 
active. The increase of tipranavir 
Cmin may be clinically relevant. 
Patients using clarithromycin at 
doses higher than 500 mg twice 
daily should be carefully monitored 
for signs of toxicity of 
clarithromycin and tipranavir. For 
patients with renal impairment dose 
reduction of clarithromycin should 
be considered (see clarithromycin 
and ritonavir product information).

Rifabutin 150 mg QD Rifabutin Cmax ↑ 70%
Rifabutin AUC ↑ 190% 
Rifabutin Cmin ↑ 114% 

25-O-desacetylrifabutin Cmax ↑ 3.2 
fold
25-O-desacetylrifabutin AUC ↑ 21 
fold
25-O-desacetylrifabutin Cmin ↑ 7.8 
fold 

Inhibition of CYP 3A4 by 
tipranavir/r

No clinically significant change is 
observed in tipranavir PK 
parameters.

Dosage reductions of rifabutin by at 
least 75% of the usual 300 mg/day 
are recommended (ie 150 mg on 
alternate days, or three times per 
week). Patients receiving rifabutin 
with Aptivus, co-administered with 
low dose ritonavir, should be 
closely monitored for emergence of 
adverse events associated with 
rifabutin therapy. Further dosage 
reduction may be necessary.

Rifampicin Co-administration of protease 
inhibitors with rifampicin 
substantially decreases protease 
inhibitor concentrations. In the case 
of tipranavir co-administered with 
low dose ritonavir, concomitant use 
with rifampicin is expected to result 
in sub-optimal levels of tipranavir 
which may lead to loss of virologic 
response and possible resistance to 
tipranavir.

Concomitant use of Aptivus, co-
administered with low dose 
ritonavir, and rifampicin is 
contraindicated (see section 4.3). 
Alternate antimycobacterial agents 
such as rifabutin should be 
considered.

Antimalarial
Halofantrine
Lumefantrine 
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase halofantrine and 
lumefantrine concentrations.

Due to their metabolic profile and 
inherent risk of inducing torsades 
de pointes, administration of 
halofantrine and lumefantrine with 
Aptivus, co-administered with low 
dose ritonavir, is not recommended 



15

Inhibition of CYP 3A4 by 
tipranavir/r

(see section 4.4).

Anticonvulsants
Carbamazepine 200 mg 
BID

Carbamazepine total* Cmax ↑ 13%
Carbamazepine total* AUC ↑ 16% 
Carbamazepine total* Cmin ↑ 23%

*Carbamazepine total = total of 
carbamazepine and epoxy-
carbamazepine (both are 
pharmacologically active moieties).

The increase in carbamazepine total 
PK parameters is not expected to 
have clinical consequences.

Tipranavir Cmin ↓ 61% (compared to 
historical data)

The decrease in tipranavir 
concentrations may result in 
decreased effectiveness.

Carbamazepine induces CYP3A4.

Carbamazepine should be used with 
caution in combination with 
Aptivus, co-administered with low 
dose ritonavir. Higher doses of 
carbamazepine (> 200 mg) may 
result in even larger decreases in 
tipranavir plasma concentrations 
(see section 4.4). 

Phenobarbital
Phenytoin
No interaction study 
performed

Phenobarbital and phenytoin induce 
CYP3A4.

Phenobarbital and phenytoin should 
be used with caution in combination 
with Aptivus, co-administered with 
low dose ritonavir (see section 4.4).

Antispasmodic
Tolterodine
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase tolterodine concentrations.

Inhibition of CYP 3A4 and CYP 
2D6 by tipranavir/r

Co-administration is not 
recommended.

Endothelin receptor antagonists
Bosentan Based on theoretical considerations, 

bosentan concentrations may 
increase upon co-administration 
with tipranavir and low dose 
ritonavir.

Inhibition of CYP 3A4 by 
tipranavir/r

Co-administration of bosentan and 
Aptivus with low dose ritonavir is 
not recommended (see section 4.4).

HMG CoA reductase inhibitors
Atorvastatin 10 mg QD Atorvastatin Cmax ↑ 8.6 fold 

Atorvastatin AUC ↑ 9.4 fold 
Atorvastatin Cmin ↑ 5.2 fold 

Tipranavir ↔

Inhibition of CYP 3A4 by 
tipranavir/r

Co-administration of atorvastatin 
and Aptivus, co-administered with 
low dose ritonavir, is not 
recommended. Other HMG-CoA 
reductase inhibitors should be 
considered such as pravastatin, 
fluvastatin or rosuvastatin (See also 
section 4.4 and rosuvastatin and 
pravastatin recommendations). In 
cases where co-administration is 
necessary, the dose of 10 mg 



16

atorvastatin daily should not be 
exceeded. It is recommended to 
start with the lowest dose and 
careful clinical monitoring is 
necessary (see section 4.4).  

Rosuvastatin  10 mg QD Rosuvastatin Cmax ↑ 123% 
Rosuvastatin AUC ↑ 37% 
Rosuvastatin Cmin ↑ 6% 

Tipranavir ↔

Mechanism unknown.

Co-administration of Aptivus, co-
administered with low dose 
ritonavir, and rosuvastatin should 
be initiated with the lowest dose 
(5 mg/day) of rosuvastatin, titrated 
to treatment response, and 
accompanied with careful clinical 
monitoring for rosuvastatin 
associated symptoms as described 
in the label of rosuvastatin.  

Pravastatin
No interaction study 
performed

Based on similarities in the 
elimination between pravastatin and 
rosuvastatin, TPV/r could increase 
the plasma levels of pravastatin. 

Mechanism unknown.

Co-administration of Aptivus, co-
administered with low dose 
ritonavir, and pravastatin should be 
initiated with the lowest dose 
(10 mg/day) of pravastatin, titrated 
to treatment response, and 
accompanied with careful clinical 
monitoring for pravastatin 
associated symptoms as described 
in the label of pravastatin.

Simvastatin
Lovastatin
No interaction study 
performed

The HMG-CoA reductase inhibitors 
simvastatin and lovastatin are 
highly dependent on CYP3A for 
metabolism.

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with simvastatin or 
lovastatin are contra-indicated due 
to an increased risk of myopathy, 
including rhabdomyolysis (see
section 4.3).

HERBAL PRODUCTS
St. John’s wort (Hypericum 
perforatum)
No interaction study 
performed

Plasma concentrations of tipranavir 
can be reduced by concomitant use 
of the herbal preparation St John’s 
wort (Hypericum perforatum). This 
is due to induction of drug 
metabolising enzymes by St John’s 
wort.

Herbal preparations containing St. 
John’s wort must not be combined 
with Aptivus, co-administered with 
low dose ritonavir. Co-
administration of Aptivus with 
ritonavir, with St. John’s wort is 
expected to substantially decrease 
tipranavir and ritonavir 
concentrations and may result in 
sub-optimal levels of tipranavir and 
lead to loss of virologic response 
and possible resistance to 
tipranavir.

Inhaled beta agonists
Salmeterol The concurrent administration of 

tipranavir and low dose ritonavir
may result in increased risk of 
cardiovascular adverse events 
associated with salmeterol, 
including QT prolongation, 
palpitations and sinus tachycardia.

Inhibition of CYP 3A4 by 

Concurrent administration of 
Aptivus, co-administered with low 
dose ritonavir, is not recommended.



17

tipranavir/r.
Oral contraceptives / Oestrogens
Ethinyl oestradiol 0.035 mg 
/ Norethindrone 1.0 mg QD
(TPV/r 750/200 mg BID)

Ethinyl oestradiol Cmax ↓ 52% 
Ethinyl oestradiol AUC ↓ 43% 

Mechanism unknown

Norethindrone Cmax ↔ 
Norethindrone AUC ↑ 27% 

Tipranavir ↔

The concomitant administration 
with Aptivus, co-administered with 
low dose ritonavir, is not 
recommended. Alternative or 
additional contraceptive measures 
are to be used when oestrogen 
based oral contraceptives are co-
administered with Aptivus and low 
dose ritonavir. Patients using 
oestrogens as hormone replacement 
therapy should be clinically 
monitored for signs of oestrogen 
deficiency (see sections 4.4 and 
4.6).

Phosphodiesterase 5 (PDE5) inhibitors
Sildenafil
Vardenafil
No interaction study 
performed

Co-administration of tipranavir and 
low dose ritonavir with PDE5 
inhibitors is expected to 
substantially increase PDE5 
concentrations and may result in an 
increase in PDE5 inhibitor-
associated adverse events including 
hypotension, visual changes and 
priapism.

CYP 3A4 inhibition by tipranavir/ r

Particular caution should be used 
when prescribing the 
phosphodiesterase (PDE5) 
inhibitors sildenafil or vardenafil in 
patients receiving Aptivus, co-
administered with low dose 
ritonavir.
A safe and effective dose has not 
been established when used with 
Aptivus, co-administered with low 
dose ritonavir. There is increased 
potential for PDE5 inhibitor-
associated adverse events (which 
include visual disturbances, 
hypotension, prolonged erection, 
and syncope).
Co-administrationof
Aptivus/ritonavir with sildenafil, 
when used to treat pulmonary 
arterial hypertension, is 
contraindicated.

Tadalafil 10 mg QD Tadalafil first-dose Cmax ↓ 22% 
Tadalafil first-dose AUC ↑ 133% 

CYP 3A4 inhibition and induction 
by tipranavir/r

Tadalafil steady-state Cmax ↓ 30%
Tadalafil steady-state AUC ↔  

No clinically significant change is 
observed in tipranavir PK 
parameters.

It is recommended to prescribe 
tadalafil after at least 7 days of 
Aptivus with ritonavir dosing.
A safe and effective dose has not 
been established when used with 
Aptivus, co-administered with low 
dose ritonavir. There is increased 
potential for PDE5 inhibitor-
associated adverse events (which 
include visual disturbances, 
hypotension, prolonged erection, 
and syncope).

Narcotic analgesics
Methadone 5 mg QD Methadone Cmax ↓ 55% 

Methadone AUC ↓ 53% 
Methadone Cmin ↓ 50% 

R-methadone Cmax ↓ 46% 
R-methadone AUC ↓ 48%

Patients should be monitored for 
opiate withdrawal syndrome. 
Dosage of methadone may need to 
be increased.



18

S-methadone Cmax ↓ 62% 
S-methadone AUC ↓ 63% 

Mechanism unknown
Meperidine
No interaction study 
performed

Tipranavir, co-administered with 
low dose ritonavir, is expected to 
decrease meperidine concentrations 
and increase normeperidine 
metabolite concentrations.

Dosage increase and long-term use 
of meperidine with Aptivus, co-
administered with low dose 
ritonavir, are not recommended due 
to the increased concentrations of 
the metabolite normeperidine which 
has both analgesic activity and CNS 
stimulant activity (e.g. seizures).

Buprenorphine/Naloxone Buprenorphine ↔ 

Norbuprenorphine AUC  79% 
Norbuprenorphine Cmax  80% 
Norbuprenorphine Cmin  80% 

Due to reduction in the levels of the 
active metabolite norbuprenorphine, 
co-administration of Aptivus, co-
administered with low dose 
ritonavir, and 
buprenorphine/naloxone may result 
in decreased clinical efficacy of 
buprenorphine. Therefore, patients 
should be monitored for opiate 
withdrawal syndrome.

Immunosupressants
Cyclosporin
Tacrolimus
Sirolimus
No interaction study 
performed

Concentrations of cyclosporin, 
tacrolimus, or sirolimus cannot be 
predicted when co-administered 
with tipranavir co-administered 
with low dose ritonavir, due to 
conflicting effect of tipranavir, co-
administered with low dose 
ritonavir, on CYP 3A and P-gp.

More frequent concentration 
monitoring of these medicinal 
products is recommended until 
blood levels have been stabilised.

Antithrombotics
Warfarin 10 mg QD First-dose tipranavir/r:

S-warfarin Cmax ↔
S-warfarin AUC ↑ 18% 

Steady-state tipranavir/r:
S-warfarin Cmax ↓ 17% 
S-warfarin AUC ↓ 12% 

Inhibition of CYP 2C9 with first-
dose tipranavir/r, then induction of 
CYP 2C9 with steady-state 
tipranavir/r

Aptivus, co-administered with low 
dose ritonavir, when combined with 
warfarin may be associated with 
changes in INR (International 
Normalised Ratio) values, and may 
affect anticoagulation 
(thrombogenic effect) or increase 
the risk of bleeding. Close clinical 
and biological (INR measurement) 
monitoring is recommended when 
warfarin and tipranavir are 
combined.

Antacids
aluminium- and magnesium-
based antacid QD 

Tipranavir Cmax ↓ 25%
Tipranavir AUC ↓ 27%

Mechanism unknown 

Dosing of Aptivus, co-administered 
with low dose ritonavir, with 
antacids should be separated by at 
least a two hours time interval. 

Proton pump inhibitors (PPIs)
Omeprazole 40 mg QD Omeprazole Cmax ↓ 73% 

Omeprazole AUC ↓ 70%

Similar effects were observed for 
the S-enantiomer, esomeprazole.  

The combined use of Aptivus, co-
administered with low dose 
ritonavir, with either omeprazole or 
esomeprazole is not recommended 
(see section 4.4). If unavoidable, 



19

Induction of CYP 2C19 by 
tipranavir/r

Tipranavir ↔

upward dose adjustments for either 
omeprazole or esomeprazole may 
be considered based on clinical 
response to therapy. There are no 
data available indicating that 
omeprazole or esomeprazole dose 
adjustments will overcome the 
observed pharmacokinetic 
interaction. Recommendations for 
maximal doses of omeprazole or 
esomeprazole are found in the 
corresponding product information. 
No tipranavir with ritonavir dose 
adjustment is required.

Lansoprazole
Pantoprazole
Rabeprazole
No interaction study 
performed

Based on the metabolic profiles of 
tipranavir/r and the proton pump 
inhibitors, an interaction can be 
expected. As a result of CYP3A4 
inhibition and CYP2C19 induction 
by tipranavir/r, lansoprazole and 
pantoprazole plasma concentrations 
are difficult to predict. Rabeprazole 
plasma concentrations might 
decrease as a result of induction of 
CYP2C19 by tipranavir/r.

The combined use of Aptivus, co-
administered with low dose 
ritonavir, with proton pump 
inhibitors is not recommended (see 
section 4.4). If the co-
administration is judged 
unavoidable, this should be done 
under close clinical monitoring.

H2-receptor antagonists
No interaction study 
performed

No data are available for H2-
receptor antagonists in combination
with tipranavir and low dose 
ritonavir.

An increase in gastric pH that may 
result from H2-receptor antagonist 
therapy is not expected to have an 
impact on tipranavir plasma 
concentrations.  

Antiarrhythmics
Amiodarone
Bepridil
Quinidine
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase amiodarone, bepridil and 
quinidine concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with amiodarone, bepridil 
or quinidine is contraindicated due 
to potential serious and/or life 
threatening events (see section 4.3)

Flecainide
Propafenone 
Metoprolol (given in heart 
failure)
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase flecainide, propafenone 
and metoprolol concentrations.

Inhibition of CYP 2D6
by tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with flecainide, 
propafenone or metoprolol is 
contraindicated (see section 4.3)

Antihistamines
Astemizole
Terfenadine
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase astemizole and terfenadine 
concentrations.

Inhibition of CYP 3A4 by 

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with astemizole or 
terfenadine is contraindicated due to 
potential serious and/or life 
threatening events (see section 4.3)



20

tipranavir/r
Ergot derivatives

Dihydroergotamine
Ergonovine
Ergotamine 
Methylergonovine
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase dihydroergotamine, 
ergonovine, ergotamine and 
methylergonovine concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with dihydroergotamine, 
ergonovine, ergotamine or 
methylergonovine is 
contraindicated due to potential 
serious and/or life threatening 
events (see section 4.3)

Gastrointestinal motility agents
Cisapride
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase cisapride concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with cisapride is 
contraindicated due to potential 
serious and/or life threatening 
events (see section 4.3)

Antipsychotics
Pimozide
Sertindole
Quetiapine
Lurasidone
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase pimozide, sertindole,  
quetiapine and lurasidone 
concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with antipsychotics such 
as pimozide, sertindole, quetiapine 
or lurasidone is contraindicated due 
to potential serious and/or life 
threatening events, including coma
(see section 4.3)

Sedatives/hypnotics
Midazolam 2 mg QD (iv)

Midazolam 5 mg QD (po)

First-dose tipranavir/r:
Midazolam Cmax ↔ 
Midazolam AUC ↑ 5.1 fold 

Steady-state tipranavir/r:
Midazolam Cmax ↓ 13%
Midazolam AUC ↑ 181% 

First-dose tipranavir/r
Midazolam Cmax ↑ 5.0 fold 
Midazolam AUC ↑ 27 fold 

Steady-state tipranavir/r
Midazolam Cmax ↑ 3.7 fold 
Midazolam AUC ↑ 9.8 fold

Ritonavir is a potent inhibitor of 
CYP3A4 and therefore affect drugs 
metabolised by this enzyme.

Concomitant use of Aptivus, co-
administered with low dose 
ritonavir, and sedative/hypnotics 
such as oral midazolam is contra-
indicated (see section 4.3). If 
Aptivus with ritonavir is 
administered with parenteral 
midazolam, close clinical 
monitoring for respiratory 
depression and/or prolonged 
sedation should be instituted and 
dosage adjustment should be 
considered.

Triazolam
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase triazolam concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with triazolam is 
contraindicated due to potential 
serious and/or life threatening 
events (see section 4.3)



21

Nucleoside analogue DNA polymerase inhibitors
Valaciclovir 500 mg single 
dose

Co-administration of valaciclovir, 
tipranavir and low dose ritonavir 
was not associated with clinically 
relevant pharmacokinetic effects.

Tipranavir: ↔
Valaciclovir: ↔

Valaciclovir and Aptivus with low 
dose ritonavir, may be co-
administered without dose 
adjustment.

Alpha 1-adrenoreceptor antagonists
Alfuzosin Based on theoretical considerations, 

co-administration of tipranavir with 
low dose ritonavir and alfuzosin 
results in increased alfuzosin 
concentrations and may result in 
hypotension.

CYP 3A4 inhibition by tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with alfuzosin is 
contraindicated. 

Others
Theophylline
No interaction study 
performed

Based on data from the cocktail 
study where caffeine (CYP1A2 
substrate) AUC was reduced by 
43%, tipranavir with ritonavir is 
expected to decrease theophylline 
concentrations.  

Induction of CYP 1A2 by 
tipranavir/r

Theophylline plasma concentrations 
should be monitored during the first 
two weeks of co-administration 
with Aptivus, co-administered with 
low dose ritonavir, and the 
theophylline dose should be 
increased as needed.

Desipramine
No interaction study 
performed

tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase desipramine concentrations

Inhibition of CYP 2D6 by 
tipranavir/r

Dosage reduction and concentration 
monitoring of desipramine is 
recommended.

Digoxin 0.25 mg QD iv 

Digoxin 0.25 mg QD po

First-dose tipranavir/r
Digoxin Cmax ↔  
Digoxin AUC ↔  

Steady-state tipranavir/r
Digoxin Cmax ↓ 20% 
Digoxin AUC ↔ 

First-dose tipranavir/r
Digoxin Cmax ↑ 93% 
Digoxin AUC ↑ 91%

Transient inhibition of P-gp by 
tipranavir/r, followed by induction 
of P-gp by tipranavir/r at steady-
state

Steady-state tipranavir/r
Digoxin Cmax ↓ 38% 
Digoxin AUC ↔  

Monitoring of digoxin serum 
concentrations is recommended 
until steady state has been obtained.

Trazodone
Interaction study performed 
only with ritonavir

In a pharmacokinetic study 
performed in healthy volunteers, 
concomitant use of low dose 
ritonavir (200 mg twice daily) with 

The combination should be used 
with caution and a lower dose of 
trazodone should be considered.



22

a single dose of trazodone led to an 
increased plasma concentration of 
trazodone (AUC increased by 
2.4 fold). Adverse events of nausea, 
dizziness, hypotension and syncope 
have been observed following co-
administration of trazodone and 
ritonavir in this study. However, it 
is unknown whether the 
combination of tipranavir with 
ritonavir might cause a larger 
increase in trazodone exposure.

Bupropion 150 mg BID Bupropion Cmax ↓ 51% 
Bupropion AUC ↓ 56%

Tipranavir ↔

The reduction of bupropion plasma 
levels is likely due to induction of 
CYP2B6 and UGT activity by RTV

If the co-administration with 
bupropion is judged unavoidable, 
this should be done under close 
clinical monitoring for bupropion 
efficacy, without exceeding the 
recommended dosage, despite the 
observed induction.

Loperamide 16 mg QD Loperamide Cmax ↓ 61% 
Loperamide AUC ↓ 51% 

Mechanism unknown

Tipranavir Cmax ↔  
Tipranavir AUC ↔  
Tipranavir Cmin ↓ 26% 

A pharmacodynamic interaction 
study in healthy volunteers 
demonstrated that administration of 
loperamide and Aptivus, co-
administered with low dose 
ritonavir, does not cause any 
clinically relevant change in the 
respiratory response to carbon 
dioxide. The clinical relevance of 
the reduced loperamide plasma 
concentration is unknown. 

Fluticasone propionate
Interaction study performed 
only with ritonavir

In a clinical study where ritonavir 
100 mg capsules bid were co-
administered with 50 µg intranasal 
fluticasone propionate (4 times 
daily) for 7 days in healthy subjects, 
the fluticasone propionate plasma 
levels increased significantly, 
whereas the intrinsic cortisol levels 
decreased by approximately 86% 
(90% confidence interval 82-89%). 
Greater effects may be expected 
when fluticasone propionate is 
inhaled. Systemic corticosteroid 
effects including Cushing's 
syndrome and adrenal suppression 
have been reported in patients 
receiving ritonavir and inhaled or 
intranasally administered 
fluticasone propionate; this could 
also occur with other corticosteroids 
metabolised via the P450 3A 
pathway e.g. budesonide. 
It is unknown whether the 
combination of tipranavir with 
ritonavir might cause a larger 
increase in fluticasone exposure.

Concomitant administration of 
Aptivus, co-administered with low 
dose ritonavir, and these 
glucocorticoids is not recommended 
unless the potential benefit of 
treatment outweighs the risk of 
systemic corticosteroid effects (see 
section 4.4). A dose reduction of the 
glucocorticoid should be considered 
with close monitoring of local and 
systemic effects or a switch to a 
glucocorticoid, which is not a 
substrate for CYP3A4 (e.g. 
beclomethasone). Moreover, in case 
of withdrawal of glucocorticoids 
progressive dose reduction may 
have to be performed over a longer 
period. The effects of high 
fluticasone systemic exposure on 
ritonavir plasma levels are as yet 
unknown.



23

4.6 Fertility, pregnancy and lactation

Contraception in males and females
Tipranavir adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe 
method of contraception should be used during treatment (see section 4.5).

Pregnancy
There are no adequate data from the use of tipranavir in pregnant women. Studies in animals have 
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Tipranavir 
should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breastfeeding
Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants 
under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue 
breast-feeding if they are receiving Aptivus.

Fertility
Clinical data on fertility are not available for tipranavir. Preclinical studies performed with tipranavir 
showed no adverse effect on fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Dizziness, somnolence, and fatigue have been reported in some patients; therefore, caution should be 
recommended when driving a car or operating machinery. If patients experience fatigue, dizziness, or 
somnolence they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable effects

Summary of the safety profile
Amongst the most common adverse reactions reported for Aptivus were gastrointestinal complaints 
such as diarrhoea and nausea as well as hyperlipidaemia. The most serious adverse reactions include 
hepatic impairment and liver toxicity. Intracranial haemorrhage (ICH) was only observed in post 
marketing experience (see section 4.4).

Aptivus co-administered with low dose ritonavir, has been associated with reports of significant liver 
toxicity. In Phase III RESIST trials, the frequency of transaminase elevations was significantly 
increased in the tipranavir with ritonavir arm compared to the comparator arm. Close monitoring is 
therefore needed in patients treated with Aptivus, co-administered with low dose ritonavir (see section 
4.4).

Limited data are currently available for the use of Aptivus, co-administered with low dose ritonavir, in 
patients co-infected with hepatitis B or C. Aptivus should therefore be used with caution in patients 
co-infected with hepatitis B or C. Aptivus should be used in this patient population only if the 
potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring.

Tabulated summary of adverse reactions
Assessment of adverse reactions from HIV-1 clinical study data is based on experience in all Phase II 
and III trials in adults treated with the 500 mg tipranavir with 200 mg ritonavir dose twice daily 
(n=1397) and are listed below by system organ class and frequency according to the following 
categories:
Very common (≥ 1/10), common (≥ 1/100 to 1/10), uncommon (≥1/1,000 to 1/100), 
rare (≥1/10,000 to 1/1,000) 

Tabulated summary of adverse reactions associated with Aptivus based on clinical studies and post-
marketing experience:



24

Blood and lymphatic 
system disorders
uncommon neutropenia, anaemia, thrombocytopenia
Immune system disorders

uncommon hypersensitivity
Metabolism and nutrition disorders

common hypertriglyceridaemia, hyperlipidaemia
uncommon anorexia, decreased appetite, weight decreased, 

hyperamylasaemia, hypercholesterolaemia, 
diabetes mellitus, hyperglycaemia

rare dehydration

Psychiatric disorders

uncommon insomnia, sleep disorder

Nervous system disorders

common headache

uncommon dizziness, neuropathy peripheral, somnolence

rare intracranial haemorrhage*

Respiratory, thoracic and 
mediastinal disorders
uncommon dyspnoea

Gastrointestinal disorders

very common diarrhoea, nausea

common vomiting, flatulence, abdominal pain, abdominal 
distension, dyspepsia

uncommon gastrooesophageal reflux disease, pancreatitis

rare lipase increased

Hepatobiliary disorders

uncommon hepatic enzyme increased (ALAT, ASAT), 
cytolytic hepatitis, liver function test abnormal 
(ALAT, ASAT), hepatitis toxic

rare hepatic failure (including fatal outcome), 
hepatitis, hepatic steatosis, hyperbilirubinaemia

Skin and subcutaneous tissue disorders

common rash

uncommon pruritus, exanthem

Musculoskeletal and connective 
tissue disorders
uncommon myalgia, muscle spasms

Renal and urinary disorders

uncommon renal failure



25

General disorders and 
administration site conditions
common fatigue

uncommon pyrexia, influenza like illness, malaise

* see section Description of selected adverse reactions “Bleeding” for source of information

Description of selected adverse reactions
The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were 
seen at higher frequency among tipranavir with ritonavir treated patients when compared with the 
comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with 
ritonavir administration. The clinical significance of these observations has not been fully explored. 

Hepatotoxicity
After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/or ASAT abnormalities was 
higher in tipranavir with ritonavir patients compared with comparator arm patients (10% and 3.4%, 
respectively). Multivariate analyses showed that baseline ALAT or ASAT above DAIDS Grade 1 and 
co-infection with hepatitis B or C were risk factors for these elevations. Most patients were able to 
continue treatment with tipranavir with ritonavir. 

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4)

Hyperlipidaemia
Grade 3 or 4 elevations of triglycerides occurred more frequently in the tipranavir with ritonavir arm 
compared with the comparator arm. At 48 weeks these rates were 25.2% of patients in the tipranavir 
with ritonavir arm and 15.6% in the comparator arm.  

Bleeding
This adverse reaction was identified through post-marketing surveillance but not observed in 
randomised controlled clinical trials (n=6300).
RESIST participants receiving tipranavir with ritonavir tended to have an increased risk of bleeding; at 
24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 
1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between 
treatment groups in coagulation parameters. The significance of this finding is being further 
monitored.
Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving tipranavir, 
many of whom had other medical conditions or were receiving concomitant medicinal products that 
may have caused or contributed to these events. However, in some cases the role of tipranavir cannot 
be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in 
patients in general, or preceding the development of ICH. Therefore, routine measurement of 
coagulation parameters is not currently indicated in the management of patients on Aptivus.
An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS 
such as those treated in the Aptivus clinical trials.

Rash
An interaction study in women between tipranavir, co-administered with low dose ritonavir, and 
ethinyl oestradiol/norethindrone demonstrated a high frequency of non-serious rash. In the RESIST 
trials, the risk of rash was similar between tipranavir with ritonavir and comparator arms (16.3% vs. 
12.5%, respectively; see section 4.4). No cases of Stevens-Johnson Syndrome or Toxic Epidermal 
Necrolysis have been reported in the clinical development programme of tipranavir.



26

Laboratory abnormalities
Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of 
patients in the tipranavir with ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST-
2) after 48-weeks were increased ASAT (6.1%), increased ALAT (9.7%), increased amylase (6.0%), 
increased cholesterol (4.2%), increased triglycerides (24.9%), and decreased white blood cell count 
(5.7%).

Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis, have been reported with protease 
inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4). Reactivation of herpes simplex and herpes 
zoster virus infections were observed in the RESIST trials.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). 
The frequency of this is unknown (see section 4.4).

Paediatric population
In an open-label, dose-finding study of tipranavir plus ritonavir (Trial 1182.14), 28 children who were 
12 years of age or above received Aptivus capsules. In general, adverse reactions were similar to those 
seen in adults, with the exception of vomiting, rash and pyrexia, which were reported more frequently
in children than in adults. The most frequently reported moderate or severe adverse reactions in the 48 
week analyses are noted below.

Most frequently reported moderate or severe adverse reactions in paediatric patients aged 12 to 
18 years who took Aptivus capsules (reported in 2 or more children, Trial 1182.14, week 48 
analyses, Full Analysis Set).

Total patients treated (N) 28
Events [N(%)]
Vomiting/ retching 3 (10.7)
Nausea 2 (7.1)
Abdominal pain1 2 (7.1)
Rash2 3 (10.7)
Insomnia 2 (7.1)
ALAT increased 4 (14.3)
1 Includes abdominal pain  (N=1) and dyspepsia (N=1).
2 Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash papular, erythema, rash 

maculo-papular, rash pruritic, and urticaria

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

Human experience with tipranavir overdose is very limited. No specific signs and symptoms of 
overdose are known. Generally, an increased frequency and higher severity of adverse reactions may 
result from overdose.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


27

There is no known antidote for tipranavir overdose. Treatment of overdose should consist of general 
supportive measures, including monitoring of vital signs and observation of the patient’s clinical 
status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric 
lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed 
substance. Since tipranavir is highly protein bound, dialysis is unlikely to be beneficial in significant 
removal of this medicine.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE09

Mechanism of action
The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the 
cleavage and maturation of viral protein precursors. Tipranavir is a non-peptidic inhibitor of the HIV-1 
protease that inhibits viral replication by preventing the maturation of viral particles.

Antiviral activity in vitro
Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models 
of T-cell infection, with 50% and 90% effective concentrations (EC50 and EC90) ranging from 0.03 to 
0.07 µM (18-42 ng/ml) and 0.07 to 0.18 µM (42-108 ng/ml), respectively. Tipranavir demonstrates 
antiviral activity in vitro against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, 
H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in 
vitro to tipranavir with EC50 values ranging from 0.164-1 µM and 0.233-0.522 µM, respectively. 
Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-
fold in conditions where human serum is present. 

Resistance
The development of resistance to tipranavir in vitro is slow and complex. In one particular in vitro
resistance experiment, an HIV-1 isolate that was 87-fold resistant to tipranavir was selected after 9 
months, and contained 10 mutations in the protease: L10F, I13V, V32I, L33F, M36I, K45I, I54V/T, 
A71V, V82L, I84V as well as a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic 
experiments showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L, 
I84V) was required to confer > 10-fold resistance to tipranavir while the full 10-mutation genotype 
conferred 69-fold resistance to tipranavir. In vitro, there is an inverse correlation between the degree 
of resistance to tipranavir and the capacity of viruses to replicate. Recombinant viruses showing ≥ 3-
fold resistance to tipranavir grow at less than 1% of the rate detected for wild type HIV-1 in the same 
conditions. Tipranavir resistant viruses which emerge in vitro from wild-type HIV-1 show decreased 
susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and 
ritonavir but remain sensitive to saquinavir. 

Through a series of multiple stepwise regression analyses of baseline and on-treatment genotypes from 
all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/or 
reduced 48-week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 
58E, 69K, 74P, 82L/T, 83D and 84V. Clinical isolates that exhibited a  10-fold decrease in tipranavir 
susceptibility harboured 8 or more tipranavir-associated mutations. In Phase II and III clinical trials, 
276 patients with on-treatment genotypes have demonstrated that the predominant emerging mutations 
with tipranavir treatment are L33F/I/V, V82T/L and I84V. Combination of all three of these is usually 
required for reduced susceptibility. Mutations at position 82 occur via two pathways: one from pre-
existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.

Cross-resistance
Tipranavir maintains significant antiviral activity (< 4-fold resistance) against the majority of HIV-1 
clinical isolates showing post-treatment decreased susceptibility to the currently approved protease 
inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir. Greater 



28

than 10-fold resistance to tipranavir is uncommon (< 2.5% of tested isolates) in viruses obtained from 
highly treatment experienced patients who have received multiple peptidic protease inhibitors.

ECG evaluation
The effect of tipranavir with low dose of ritonavir on the QTcF interval was measured in a study in 
which 81 healthy subjects received the following treatments twice daily for 2.5 days: 
tipranavir/ritonavir (500/200 mg), tipranavir/ritonavir at a supra-therapeutic dose (750/200 mg), and 
placebo/ritonavir (-/200 mg). After baseline and placebo adjustment, the maximum mean QTcF 
change was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the 500/200 mg dose and 8.3 ms (1-sided 95% 
Upper CI: 10.8 ms) for the supra-therapeutic 750/200 mg dose. Hence tipranavir at therapeutic dose 
with low dose of ritonavir did not prolong the QTc interval but may do so at supratherapeutic dose.

Clinical pharmacodynamic data
This indication is based on the results of two phase III studies, performed in highly pre-treated adult 
patients (median number of 12 prior antiretroviral agents) with virus resistant to protease inhibitors 
and of one phase II study investigating pharmacokinetics, safety and efficacy of Aptivus in mostly 
treatment-experienced adolescent patients aged 12 to 18 years.

The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1 
and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts. RESIST-1 and 
RESIST-2 are ongoing, randomised, open-label, multicentre studies in HIV-positive, triple-class 
experienced patients, evaluating treatment with 500 mg tipranavir co-administered with low dose 
ritonavir (200 mg; twice daily) plus an optimised background regimen (OBR) individually defined for 
each patient based on genotypic resistance testing and patient history. The comparator regimen 
included a ritonavir-boosted PI (also individually defined) plus an OBR. The ritonavir-boosted PI was 
chosen from among saquinavir, amprenavir, indinavir or lopinavir/ritonavir.  

All patients had received at least two PI-based antiretroviral regimens and were failing a PI-based 
regimen at the time of study entry. At least one primary protease gene mutation from among 30N, 46I, 
46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than 
two mutations on codons 33, 82, 84 or 90.

After Week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of 
virologic response had the option of discontinuing treatment and switching over to tipranavir with 
ritonavir in a separate roll-over study. 

The 1483 patients included in the primary analysis had a median age of 43 years (range 17-80), were 
86% male, 75% white, 13% black and 1% Asian. In the tipranavir and comparator arms median 
baseline CD4 cell counts were 158 and 166 cells/mm3, respectively, (ranges 1-1893 and 1-
1184 cells/mm3); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log10 copies/ml, respectively 
(ranges 2.34-6.52 and 2.01-6.76 log10 copies/ml). 

Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. In both studies, a total of 
67% patient viruses were resistant and 22% were possibly resistant to the pre-selected comparator PIs. 
A total of 10% of patients had previously used enfuvirtide. Patients had baseline HIV-1 isolates with a 
median of 16 HIV-1 protease gene mutations, including a median of 3 primary protease gene 
mutations D30N, L33F/I, V46I/L, G48V, I50V, V82A/F/T/L, I84V, and L90M. With respect to 
mutations on codons 33, 82, 84 and 90 approximately 4% had no mutations, 24% had mutations at 
codons 82 (less than 1% of patients had the mutation V82L) and 90, 18% had mutations at codons 84 
and 90 and 53% had at least one key mutation at codon 90. One patient in the tipranavir arm had four 
mutations. In addition the majority of participants had mutations associated with both NRTI and 
NNRTI resistance. Baseline phenotypic susceptibility was evaluated in 454 baseline patient samples.  
There was an average decrease in susceptibility of 2-fold wild type (WT) for tipranavir, 12-fold WT 
for amprenavir, 55-fold WT for atazanavir, 41-fold WT for indinavir, 87-fold WT for lopinavir, 41-
fold WT for nelfinavir, 195-fold WT for ritonavir, and 20-fold WT for saquinavir.



29

Combined 48-week treatment response (composite endpoint defined as patients with a confirmed 
1 log RNA drop from baseline and without evidence of treatment failure) for both studies was 34% 
in the tipranavir with ritonavir arm and 15% in the comparator arm. Treatment response is presented 
for the overall population (displayed by enfuvirtide use), and detailed by PI strata for the subgroup of 
patients with genotypically resistant strains in the Table below. 

Treatment response* at week 48 (pooled studies RESIST-1 and RESIST-2 in treatment-
experienced patients)

RESIST study Tipranavir/RTV CPI/RTV** p-value

n (%) N n (%) N
Overall population
FAS
PP

255 (34.2)
171 (37.7)

746
454

114 (15.5)
74 (17.1)

737
432

0.0001
0.0001

- with ENF (FAS) 85 (50.0) 170 28 (20.7) 135 0.0001
- without ENF (FAS) 170 (29.5) 576 86 (14.3) 602 0.0001

Genotypically Resistant
LPV/rtv  
FAS
PP

66 (28.9)
47 (32.2)

228
146

23 (9.5)
13 (9.1)

242
143

0.0001
0.0001

APV/rtv
FAS
PP

50 (33.3)
38 (39.2)

150
97

22 (14.9)
17 (18.3)

148
93

0.0001
0.0010

SQV/rtv
FAS
PP

22 (30.6)
11 (28.2)

72
39

5 (7.0)
2 (5.7)

71
35

0.0001
0.0650

IDV/rtv
FAS
PP

6 (46.2)
3 (50.0)

13
6

1 (5.3)
1 (7.1)

19
14

0.0026
0.0650

* Composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without 
evidence of treatment failure 
** Comparator PI/RTV: LPV/r 400 mg/100 mg twice daily (n=358), IDV/r 800 mg/100 mg twice 
daily (n=23), SQV/r 1000 mg/100 mg twice daily or 800 mg/200 mg twice daily (n=162), APV/r 
600 mg/100 mg twice daily (n=194)
ENF Enfuvirtide; FAS Full Analysis Set; PP Per Protocol; APV/rtv Amprenavir/ritonavir; IDV/rtv
Indinavir/ritonavir; LPV/rtv Lopinavir/ritonavir; SQV/rtv Saquinavir/ritonavir

Combined 48-week median time to treatment failure for both studies was 115 days in the tipranavir 
with ritonavir arm and 0 days in the comparator arm (no treatment response was imputed to day 0).

Through 48 weeks of treatment, the proportion of patients in the tipranavir with ritonavir arm 
compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/ml was 30% and 14% 
respectively, and with HIV-1 RNA < 50 copies/ml was 23% and 10% respectively. Among all 
randomised and treated patients, the median change from baseline in HIV-1 RNA at the last 
measurement up to Week 48 was -0.64 log10 copies/ml in patients receiving tipranavir with ritonavir 
versus -0.22 log10 copies/ml in the comparator PI/ritonavir arm.

Among all randomised and treated patients, the median change from baseline in CD4+ cell count at 
the last measurement up to Week 48 was +23 cells/mm3 in patients receiving tipranavir with ritonavir 
(N=740) versus +4 cells/mm3 in the comparator PI/ritonavir (N=727) arm.

The superiority of tipranavir co-administered with low dose ritonavir over the comparator protease 
inhibitor/ritonavir arm was observed for all efficacy parameters at week 48. It has not been shown that 
tipranavir is superior to these boosted comparator protease inhibitors in patients harbouring strains 
susceptible to these protease inhibitors. RESIST data also demonstrate that tipranavir co-administered 



30

with low dose ritonavir exhibits a better treatment response at 48 weeks when the OBR contains 
genotypically available antiretroviral agents (e.g. enfuvirtide).

At present there are no results from controlled trials evaluating the effect of tipranavir on clinical 
progression of HIV.

Paediatric population
HIV-positive, paediatric patients, aged 2 through 18 years, were studied in a randomized, open-label, 
multicenter study (trial 1182.14). Patients were required to have a baseline HIV-1 RNA concentration 
of at least 1500 copies/ml, were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years) 
and randomized to receive one of two tipranavir with ritonavir dose regimens: 375 mg/m2/150 mg/m2

dose, compared to the 290 mg/m2/115 mg/m2 dose, plus background therapy of at least two non-
protease inhibitor antiretroviral medicinal products, optimized using baseline genotypic resistance 
testing. All patients initially received Aptivus oral solution. Paediatric patients who were 12 years or 
older and received the maximum dose of 500 mg/200 mg twice daily could change to Aptivus capsules 
from study day 28. The trial evaluated pharmacokinetics, safety and tolerability, as well as virologic 
and immunologic responses through 48 weeks.  

No data are available on the efficacy and safety of Aptivus capsules in children less than 12 years of 
age. Since Aptivus capsules and oral solution are not bioequivalent, results obtained with the oral 
solution cannot be extrapolated to the capsules (see also section 5.2). In patients with a body surface 
area of less than 1.33 m2 appropriate dose adjustments cannot be achieved with the capsule 
formulation.

The baseline characteristics and the key efficacy results at 48 weeks for the paediatric patients 
receiving Aptivus capsules are displayed in the tables below. Data on the 29 patients who switched to 
capsules during the first 48 weeks are presented. Due to limitations in the study design (e.g. non-
randomized switch allowed according to patient/clinician decision), any comparisons between patients 
taking capsules and oral solution are not meaningful.

Baseline characteristics for patients 12 – 18 years of age who took capsule

Variable Value
Number of Patients 29
Age-Median (years) 15.1
Gender % Male 48.3%
Race % White 69.0%

% Black 31.0%
% Asian 0.0%

Baseline HIV-1 RNA 
(log10 copies/ml)

Median 
(Min – Max)

4.6 (3.0 – 6.8)

% with VL  > 
100,000 copies/ml

27.6%

Baseline CD4+ 
(cells/mm3)

Median
(Min – Max)

330 (12 – 593)

% ≤ 200 27.6%

Baseline % CD4+ cells Median 
(Min – Max)

18.5% (3.1% –
37.4%)

Previous ADI* % with Category C 29.2%
Treatment history % with any ARV 96.6%

Median # previous 
NRTIs

5

Median # previous 
NNRTIs

1

Median # previous 
PIs

3



31

* AIDS defining illness

Key efficacy results at 48 weeks for patients 12 – 18 years of age who took capsule

Endpoint Result
Number of patients 29
Primary efficacy  endpoint: 
% with VL < 400 

31.0%

Median change from baseline
in log10 HIV-1 RNA (copies/ml) 

-0.79

Median change from baseline
in CD4+ cell count (cells/mm3) 

39

Median change from baseline
in % CD4+ cells 

3%

Analyses of tipranavir resistance in treatment experienced patients
Tipranavir with ritonavir response rates in the RESIST studies were assessed by baseline tipranavir 
genotype and phenotype.  Relationships between baseline phenotypic susceptibility to tipranavir, 
primary PI mutations, protease mutations at codons 33, 82, 84 and 90, tipranavir resistance-associated 
mutations, and response to tipranavir with ritonavir therapy were assessed.

Of note, patients in the RESIST studies had a specific mutational pattern at baseline of at least one 
primary protease gene mutation among codons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 
90M, and no more than two mutations on codons 33, 82, 84 or 90.

The following observations were made:

 Primary PI mutations
Analyses were conducted to assess virological outcome by the number of primary PI mutations (any 
change at protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90) present at baseline. 
Response rates were higher in tipranavir with ritonavir patients than comparator PI boosted with 
ritonavir in new enfuvirtide patients, or patients without new enfuvirtide. However, without new 
enfuvirtide some patients began to lose antiviral activity between weeks 4 and 8.

 Mutations at protease codons 33, 82, 84 and 90
A reduced virological response was observed in patients with viral strains harbouring two or more 
mutations at HIV protease codons 33, 82, 84 or 90, and not receiving new enfuvirtide.

 Tipranavir resistance-associated mutations
Virological response to tipranavir with ritonavir therapy has been evaluated using a tipranavir-
associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients. This score 
(counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or 
reduced viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 
69K, 74P, 82L/T, 83D and 84V) was applied to baseline viral protease sequences. A correlation 
between the tipranavir mutation score and response to tipranavir with ritonavir therapy at week 48 has 
been established. 

This score has been determined from the selected RESIST patient population having specific mutation 
inclusion criteria and therefore extrapolation to a wider population mandates caution.

At 48-weeks, a higher proportion of patients receiving tipranavir with ritonavir achieved a treatment 
response in comparison to the comparator protease inhibitor/ritonavir for nearly all of the possible 
combinations of genotypic resistance mutations (see table below).



32

Proportion of patients achieving treatment response at Week 48 (confirmed ≥1 log10 copies/ml 
decrease in viral load compared to baseline), according to tipranavir baseline mutation score 
and enfuvirtide use in RESIST patients

New ENF No New 
ENF*

Number of 
TPV Score 
Mutations**

TPV/r TPV/r 

0,1 73% 53%
2 61% 33%
3 75% 27%
4 59% 23%

≥ 5 47% 13%
All patients 61% 29%

* Includes patients who did not receive ENF and those who were previously treated with and 
continued ENF
**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, 
I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V
ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

Sustained HIV-1 RNA decreases up to week 48 were mainly observed in patients who received 
tipranavir with ritonavir and new enfuvirtide. If patients did not receive tipranavir with ritonavir with 
new enfuvirtide, diminished treatment responses at week 48 were observed, relative to new enfuvirtide 
use (see Table below).

Mean decrease in viral load from baseline to week 48, according to tipranavir baseline mutation 
score and enfuvirtide use in RESIST patients

New ENF No New 
ENF*

Number of  
TPV Score 
Mutations**

TPV/r TPV/r 

0, 1 -2.3 -1.6
2 -2.1 -1.1
3 -2.4 -0.9
4 -1.7 -0.8

≥ 5 -1.9 -0.6
All patients -2.0 -1.0

* Includes patients who did not receive ENF and those who were previously treated with and 
continued ENF
** Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, 
M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V
ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

 Tipranavir phenotypic resistance
Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing 
virological response.  Isolates with baseline fold change of >0 to 3 are considered susceptible; isolates 
with >3 to 10 fold changes have decreased susceptibility; isolates with >10 fold changes are resistant.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to 
change with additional data, and it is recommended to always consult current interpretation systems 
for analysing resistance test results.



33

5.2 Pharmacokinetic properties

In order to achieve effective tipranavir plasma concentrations and a twice daily dosing regimen, 
coadministration of tipranavir with low dose ritonavir twice daily is essential (see section 4.2). 
Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (P-gp) 
efflux pump and possibly intestinal cytochrome P450 CYP3A as well. As demonstrated in a dose-
ranging evaluation in 113 HIV-negative healthy male and female volunteers, ritonavir increases AUC0-
12h, Cmax and Cmin and decreases the clearance of tipranavir. 500 mg Tipranavir co-administered with 
low dose ritonavir (200 mg; twice daily) was associated with a 29-fold increase in the geometric mean 
morning steady-state trough plasma concentrations compared to tipranavir 500 mg twice daily without 
ritonavir. 

Absorption
Absorption of tipranavir in humans is limited, though no absolute quantification of absorption is 
available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor and appears to be a potent P-gp inducer 
as well. Data suggest that, although ritonavir is a P-gp inhibitor, the net effect of Aptivus, co-
administered with low dose ritonavir, at the proposed dose regimen at steady-state, is P-gp induction. 
Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon 
the dosage used. With repeated dosing, tipranavir plasma concentrations are lower than predicted from 
single dose data, presumably due to hepatic enzyme induction. Steady-state is attained in most subjects 
after 7 days of dosing. Tipranavir, co-administered with low dose ritonavir, exhibits linear 
pharmacokinetics at steady state.

Dosing with Aptivus capsules 500 mg twice daily concomitant with 200 mg ritonavir twice daily for 2 
to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration (Cmax) 
of 94.8 ± 22.8 µM for female patients (n=14) and 77.6 ± 16.6 µM for male patients (n=106), occurring 
approximately 3 hours after administration. The mean steady-state trough concentration prior to the 
morning dose was 41.6 ± 24.3 µM for female patients and 35.6 ± 16.7 µM for male patients. 
Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 µM•h (CL=1.15 l/h) for female 
patients and 710 ± 207 µM•h (CL=1.27 l/h) for male patients. The mean half-life was 5.5 (females) or 
6.0 hours (males). 

Effects of food on oral absorption
Food improves the tolerability of tipranavir with ritonavir. Therefore Aptivus, co-administered with 
low dose ritonavir, should be given with food. 

Absorption of tipranavir, co-administered with low dose ritonavir, is reduced in the presence of 
antacids (see section 4.5). 

Distribution
Tipranavir is extensively bound to plasma proteins (>99.9%). From clinical samples of healthy 
volunteers and HIV-1 positive subjects who received tipranavir without ritonavir the mean fraction of 
tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015%  0.006%; 
HIV-positive subjects 0.019%  0.076%). Total plasma tipranavir concentrations for these samples 
ranged from 9 to 82 M. The unbound fraction of tipranavir appeared to be independent of total 
concentration over this concentration range.  

No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal 
fluid or semen.

Biotransformation
In vitro metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant 
CYP isoform involved in tipranavir metabolism. 

The oral clearance of tipranavir decreased after the addition of ritonavir which may represent 
diminished first-pass clearance of the substance at the gastrointestinal tract as well as the liver. 



34

The metabolism of tipranavir in the presence of low dose ritonavir is minimal. In a 14C-tipranavir 
human study (500 mg 14C-tipranavir with 200 mg ritonavir,  twice daily), unchanged tipranavir was 
predominant and accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or 
12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2% 
or less of the plasma radioactivity). In faeces, unchanged tipranavir represented the majority of faecal 
radioactivity (79.9% of faecal radioactivity). The most abundant faecal metabolite, at 4.9% of faecal 
radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir 
was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 
11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.

Elimination
Administration of 14C-tipranavir to subjects (n = 8) that received 500 mg tipranavir with 200 mg 
ritonavir; twice daily dosed to steady-state demonstrated that most radioactivity (median 82.3%) was 
excreted in faeces, while only a median of 4.4% of the radioactive dose administered was recovered in 
urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The 
effective mean elimination half-life of tipranavir with ritonavir in healthy volunteers (n = 67) and 
HIV-infected adult patients (n = 120) was approximately 4.8 and 6.0 hours, respectively, at steady 
state following a dose of 500 mg/200 mg twice daily with a light meal. 

Special populations
Although data available at this stage are currently limited to allow a definitive analysis, they suggest 
that the pharmacokinetic profile is unchanged in older people and comparable between races. By 
contrast, evaluation of the steady-state plasma tipranavir trough concentrations at 10-14 h after dosing 
from the RESIST-1 and RESIST-2 studies demonstrate that females generally had higher tipranavir 
concentrations than males. After four weeks of Aptivus 500 mg with 200 mg ritonavir (twice daily) 
the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males. 
This difference in concentrations does not warrant a dose adjustment.

Renal impairment
Tipranavir pharmacokinetics have not been studied in patients with renal impairment. However, since 
the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in 
patients with renal impairment.

Hepatic impairment
In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 controls, the single 
and multiple dose exposure of tipranavir and ritonavir were increased in patients with hepatic 
impairment but still within the range observed in clinical studies.  No dosing adjustment is required in 
patients with mild hepatic impairment but patients should be closely monitored (see sections 4.2 and 
4.4).

The influence of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment on the 
multiple dose pharmacokinetics of either tipranavir or ritonavir has so far not been investigated. 
tipranavir is contraindicated in moderate or severe hepatic impairment (see sections 4.2 and 4.3).

Paediatric population
The oral solution has been shown to have greater bioavailability than the soft capsule formulation.

5.3 Preclinical safety data

Animal toxicology studies have been conducted with tipranavir alone, in mice, rats and dogs, and co-
administered with ritonavir (3.75:1 w/w ratio) in rats and dogs. Studies with co-administration of 
tipranavir and ritonavir did not reveal any additional toxicological effects when compared to those 
seen in the tipranavir single agent toxicological studies.

The predominant effects of repeated administration of tipranavir across all species toxicologically 
tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy). The 
effects were reversible with termination of treatment. Additional changes included bleeding in rats at 



35

high doses (rodents specific). Bleeding observed in rats was associated with prolonged prothrombin 
time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent 
factors. The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol 
polyethylene glycol 1000 succinate) from 2,322 IU/m² upwards in rats resulted in a significant 
increase in effects on coagulation parameters, bleeding events and death. In preclinical studies of 
tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir 
and vitamin E has not been studied in dogs. 

The majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which 
are equivalent to or even below the human exposure levels at the recommended clinical dose. 

In in vitro studies, tipranavir was found to inhibit platelet aggregation when using human platelets (see 
section 4.4) and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure 
observed in patients receiving Aptivus with ritonavir. The clinical implications of these findings are 
not known.

In a study conducted in rats with tipranavir at systemic exposure levels (AUC) equivalent to human 
exposure at the recommended clinical dose, no adverse effects on mating or fertility were observed. At 
maternal doses producing systemic exposure levels similar to or below those at the recommended 
clinical dose, tipranavir did not produce teratogenic effects. At tipranavir exposures in rats at 0.8-fold 
human exposure at the clinical dose, foetal toxicity (decreased sternebrae ossification and body 
weights) was observed. In pre- and post-natal development studies with tipranavir in rats, growth 
inhibition of pups was observed at maternally toxic doses approximating 0.8-fold human exposure. 

Carcinogenicity studies of tipranavir in mice and rats revealed tumourigenic potential specific for 
these species, which are regarded as of no clinical relevance. Tipranavir showed no evidence of 
genetic toxicity in a battery of in vitro and in vivo tests. 

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents 
Macrogolglycerol ricinoleate
Ethanol 
Mono/diglycerides of caprylic/capric acid
Propylene glycol 
Purified water
Trometamol
Propyl gallate

Capsule shell 
Gelatin
Red iron oxide (E172)
Propylene glycol 
Purified water
‘Sorbitol special-glycerin blend’ (d-sorbitol, 1,4 sorbitan, mannitol and glycerin)
Titanium dioxide (E171)

Black printing ink
Propylene glycol

Black iron oxide (E172)
Polyvinyl acetate phthalate
Macrogol
Ammonium hydroxide



36

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

In use storage: 60 days (below 25°C), after first opening of the bottle. It is advisable that the patient 
writes the date of opening the bottle on the label and/or carton.

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C). 

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with two-piece child-resistant closure (outer and inner shell 
polypropylene, with a pulpboard/aluminium liner). Each bottle contains 120 soft capsules.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/05/315/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 October 2005
Date of latest renewal: 19 June 2015

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu/ 



37

1. NAME OF THE MEDICINAL PRODUCT

Aptivus 100 mg/ml oral solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral solution contains 100 mg tipranavir. 

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral solution.

Clear yellow viscous liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Aptivus, co-administered with low dose ritonavir, is indicated for combination antiretroviral treatment 
of HIV-1 infection in highly pre-treated children from 2 to 12 years of age with virus resistant to 
multiple protease inhibitors. Aptivus should only be used as part of an active combination 
antiretroviral regimen in patients with no other therapeutic options (see sections 4.4 and 5.1). 

In deciding to initiate treatment with Aptivus, co-administered with low dose ritonavir, careful 
consideration should be given to the treatment history of the individual patient and the patterns of 
mutations associated with different agents. Genotypic or phenotypic testing (when available) and 
treatment history should guide the use of Aptivus. Initiation of treatment should take into account the 
combinations of mutations which may negatively impact the virological response to Aptivus, co-
administered with low dose ritonavir (see section 5.1).

4.2 Posology and method of administration

Aptivus must always be given with low dose ritonavir as a pharmacokinetic enhancer, and in 
combination with other antiretroviral medicinal products. The Summary of Product Characteristics of 
ritonavir must therefore be consulted prior to initiation of therapy with Aptivus (especially as regards 
the contraindications, warnings and undesirable effects sections).

Aptivus should be prescribed by physicians who are experienced in the treatment of HIV-1 infection. 

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

Posology
The recommended dose for children (age 2 to 12 years) is 375 mg/m2 Aptivus co-administered with 
150 mg/m2 ritonavir, twice daily. The paediatric dose should not exceed the 500 mg/200 mg dose.

Aptivus/ritonavir dose (375 mg/m2 Aptivus + 150 mg/m2 ritonavir)

BSA Range 
(m2)

Dose 
Aptivus

(mg)
Volume 

Aptivus (ml)

Dose 
ritonavir

(mg)

Volume 
ritonavir

(ml)
0.37 – 0.42 140 1.4 56 0.7
0.43 – 0.47 160 1.6 63 0.8



38

0.48 – 0.52 180 1.8 71 0.9
0.53 – 0.58 200 2 79 1
0.59 – 0.63 220 2.2 87 1.1
0.64 – 0.68 240 2.4 95 1.2

0.69 - 0.74 260 2.6 103 1.3
0.75 – 0.79 280 2.8 111 1.4
0.80 – 0.84 300 3 119 1.5
0.85 – 0.90 320 3.2 127 1.6
0.91 – 0.95 340 3.4 135 1.7
0.96 – 1.00 360 3.6 143 1.8

1.01 - 1.06 380 3.8 151 1.9
1.07 – 1.11 400 4 159 2
1.12 – 1.16 420 4.2 167 2.1
1.17 – 1.22 440 4.4 174 2.2
1.23 – 1.27 460 4.6 182 2.3
1.28 – 1.32 480 4.8 190 2.4

> 1.33 500 5 200 2.5

Doses of ritonavir lower than 150 mg/m2 twice daily, should not be used as they might alter the 
efficacy profile of the combination.

Aptivus is available as soft capsules for adults and adolescents from 12 years of age (please refer to 
the respective SmPC for further details). Patients treated with Aptivus and reaching the age of 12 years 
should be switched to the capsule formulation (see sections 4.4 and 5.1).

Missed dose
Patients should be advised of the need to take Aptivus and ritonavir every day as prescribed. If a dose 
is missed by more than 5 hours, the patient should be instructed to wait and then to take the next dose 
of tipranavir and ritonavir at the regularly scheduled time. If a dose is missed by less than 5 hours, the 
patient should be instructed to take the missed dose immediately, and then to take the next dose of 
tipranavir and ritonavir at the regularly scheduled time.

Liver impairment
Tipranavir is metabolised by the hepatic system. Liver impairment could therefore result in an increase 
of tipranavir exposure and a worsening of its safety profile. Therefore, Aptivus should be used with 
caution, and with increased monitoring frequency, in patients with mild hepatic impairment (Child-
Pugh Class A). Aptivus is contraindicated in patients with moderate or severe (Child-Pugh Class B or 
C) hepatic impairment (see sections 4.3, 4.4 and 5.2).

Renal impairment
No dosage adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of Aptivus in children under 2 years of age has not been established. No data 
are available. 

Method of administration 
Oral use.
Aptivus oral solution co-administered with low dose oral solution ritonavir should be taken with food 
(see section 5.2).

4.3 Contraindications

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

Patients with moderate or severe (Child-Pugh B or C) hepatic impairment. 



39

Combination of rifampicin with Aptivus with concomitant low dose ritonavir is contraindicated (see 
section 4.5).

Herbal preparations containing St John’s wort (Hypericum perforatum) due to the risk of decreased 
plasma concentrations and reduced clinical effects of tipranavir (see section 4.5).

Co-administration of Aptivus with low dose ritonavir, with active substances that are highly dependent 
on CYP3A for clearance, and for which elevated plasma concentrations are associated with serious 
and/or life-threatening events. These active substances include antiarrhythmics (such as amiodarone, 
bepridil, quinidine), antihistamines (such as astemizole, terfenadine), ergot derivatives (such as 
dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility agents (such 
as cisapride), antipsychotics (such as pimozide, sertindole, quetiapine, lurasidone), sedatives/hypnotics 
(such as orally administered midazolam and triazolam) and HMG-CoA reductase inhibitors (such as 
simvastatin and lovastatin) (see section 4.5). Also the use of the alpha-1 adrenoceptor antagonist 
alfuzosin, and sildenafil when used for the treatment of pulmonary arterial hypertension. In addition, 
co-administration of Aptivus with low dose ritonavir, and medicinal products that are highly 
dependent on CYP2D6 for clearance, such as the antiarrhythmics flecainide, propafenone and 
metoprolol given in heart failure (see section 4.5).

Co-administration of colchicine with Aptivus/ritonavir in patients with renal or hepatic impairment 
(see section 4.5).

4.4 Special warnings and precautions for use

Aptivus must be administered with low dose ritonavir to ensure its therapeutic effect (see section 4.2). 
Failure to correctly co-administer tipranavir with ritonavir will result in reduced plasma levels of 
tipranavir that may be insufficient to achieve the desired antiviral effect. Patients should be instructed 
accordingly. 

Aptivus is not a cure for HIV-1 infection or AIDS. Patients receiving Aptivus or any other 
antiretroviral therapy may continue to develop opportunistic infections and other complications of 
HIV-1 infection.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission 
should be taken in accordance with national guidelines.

Switching from Aptivus capsules to the oral solution
Aptivus capsules are not interchangeable with the oral solution. Compared to the capsules, tipranavir 
exposure is higher when administering the same dose as oral solution. Also, the composition of the 
oral solution is different from that of the capsules, with the high vitamin E content being especially 
noteworthy. Both of these factors may contribute to an increased risk of adverse reactions (type, 
frequency and/or severity). Therefore patients should not be switched from Aptivus capsules to 
Aptivus oral solution (see sections 5.1 and 5.2). 

Switching from Aptivus oral solution to the capsules
Aptivus oral solution is not interchangeable with the capsules. Compared to the oral solution, 
tipranavir exposure is lower when administering the same dose as capsules. However, children 
previously treated with Aptivus oral solution and becoming 12 years of age should be switched to 
capsules, particularly because of the more favourable safety profile of the capsules. It has to be noted 
that the switch from the oral solution to the capsule formulation of Aptivus could be associated with 
decreased exposure. Therefore, it is recommended that patients switching from Aptivus oral solution 
to capsules at the age of 12 years are closely monitored for the virologic response of their 
antiretroviral regimen (see sections 5.1 and 5.2).



40

Liver disease
Aptivus is contraindicated in patients with moderate or severe (Child-Pugh Class B or C) hepatic 
insufficiency. Limited data are currently available for the use of Aptivus, co-administered with low 
dose ritonavir, in patients co-infected with hepatitis B or C. Patients with chronic hepatitis B or C and 
treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal 
hepatic adverse reaction. Aptivus should be used in this patient population only if the potential benefit 
outweighs the potential risk, and with increased clinical and laboratory monitoring. In the case of 
concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of 
Product Characteristics for these medicinal products.

Patients with mild hepatic impairment (Child-Pugh Class A) should be closely monitored.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased 
frequency of liver function abnormalities during combination therapy and should be monitored 
according to standard practice. Aptivus with ritonavir should be discontinued once signs of worsening 
liver function occur in patients with pre-existing liver disease.

Aptivus co-administered with low dose ritonavir, has been associated with reports of clinical hepatitis 
and hepatic decompensation, including some fatalities. These have generally occurred in patients with 
advanced HIV disease taking multiple concomitant medicinal products. Caution should be exercised 
when administering Aptivus to patients with liver enzyme abnormalities or with a history of hepatitis. 
Increased ALAT/ASAT monitoring should be considered in these patients.

Aptivus therapy should not be initiated in patients with pre-treatment ASAT or ALAT greater than 5 
times the Upper Limit Normal (ULN) until baseline ASAT/ALAT is stabilised at less than 5X ULN, 
unless the potential benefit justifies the potential risk.

Aptivus therapy should be discontinued in patients experiencing ASAT or ALAT elevations greater 
than 10X ULN, or developing signs or symptoms of clinical hepatitis during therapy. If another cause 
is identified (e.g. acute hepatitis A, B or C virus, gallbladder disease, other medicinal products), then 
rechallenge with Aptivus may be considered when ASAT/ALAT have returned to the patient’s 
baseline levels.

Liver monitoring
Monitoring of hepatic tests should be done prior to initiation of therapy, after two, four and then every 
four weeks until 24 weeks, and then every eight to twelve weeks thereafter. Increased monitoring (i.e. 
prior to initiation of therapy, every two weeks during the first three months of treatment, then monthly 
until 48 weeks, and then every eight to twelve weeks thereafter) is warranted when Aptivus and low 
dose ritonavir are administered to patients with elevated ASAT and ALAT levels, mild hepatic 
impairment, chronic hepatitis B or C, or other underlying liver disease.

Treatment-naïve patients
In a study performed in antiretroviral naïve adult patients, tipranavir 500 mg with ritonavir 200 mg 
twice daily, as compared to lopinavir/ritonavir, was associated with an excess in the occurrence of 
significant (grade 3 and 4) transaminase elevations without any advantage in terms of efficacy (trend 
towards a lower efficacy). The study was prematurely stopped after 60 weeks.
Therefore, tipranavir with ritonavir should not be used in treatment-naïve patients.

Renal impairment
Since the renal clearance of tipranavir is negligible, increased plasma concentrations are not expected 
in patients with renal impairment.

Haemophilia
There have been reports of increased bleeding, including spontaneous skin haematomas and 
haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some 
patients additional Factor VIII was given. In more than half of the reported cases, treatment with 
protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal 



41

relationship has been evoked, although the mechanism of action had not been elucidated. 
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. 

Bleeding
RESIST participants receiving Aptivus with ritonavir tended to have an increased risk of bleeding; at 
24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 
1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between 
treatment groups in coagulation parameters. The significance of this finding is being further 
monitored.

Fatal and non-fatal intracranial haemorrhages (ICH) have been reported in patients receiving Aptivus, 
many of whom had other medical conditions or were receiving concomitant medicinal products that 
may have caused or contributed to these events. However, in some cases the role of Aptivus cannot be 
excluded. No pattern of abnormal haematological or coagulation parameters has been observed in 
patients in general, or preceding the development of ICH. Therefore, routine measurement of 
coagulation parameters is not currently indicated in the management of patients on Aptivus.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS 
such as those treated in the Aptivus clinical trials.

In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels 
consistent with exposures observed in patients receiving Aptivus with ritonavir.

In rats, co-administration with vitamin E increased the bleeding effects of tipranavir (see section 5.3).

Aptivus, co-administered with low dose ritonavir, should be used with caution in patients who may be 
at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving 
medicinal products known to increase the risk of bleeding such as antiplatelet agents and 
anticoagulants or who are taking supplemental vitamin E. Patients taking Aptivus oral solution should 
be advised not to take any supplemental vitamin E.

Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. A higher increase of blood lipids were seen with tipranavir/ritonavir 
than with comparators (other protease inhibitors) in clinical trials. For monitoring of blood lipids and 
glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed 
as clinically appropriate.

Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, 
such reactions have been observed within the first few weeks or months of initiation of CART. 
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and 
pneumocystis pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted 
when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in 
clinical studies with Aptivus, co-administered with low dose ritonavir.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment.

Rash
Mild to moderate rashes including urticarial rash, maculopapular rash, and photosensitivity have been 
reported in subjects receiving Aptivus, co-administered with low dose ritonavir. At 48-weeks in Phase 



42

III trials, rash of various types was observed in 15.5% males and 20.5% females receiving Aptivus co-
administered with low dose ritonavir. Additionally, in one interaction trial, in healthy female 
volunteers administered a single dose of ethinyl oestradiol followed by Aptivus co-administered with 
low dose ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, 
throat tightness, or generalized pruritus has been reported in both men and women receiving Aptivus
co-administered with low dose ritonavir. In the paediatric clinical trial, the frequency of rash (all 
grades, all causality) through 48 weeks of treatment was higher than in adult patients.

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.

Interactions
The interaction profile of tipranavir, co-administered with low dose ritonavir, is complex. The 
mechanisms and potential mechanisms contributing to the interaction profile of tipranavir are 
described (see section 4.5).

Abacavir and zidovudine 
The concomitant use of Aptivus, co-administered with low dose ritonavir, with zidovudine or 
abacavir, results in a significant decrease in plasma concentration of these nucleoside reverse 
transcriptase inhibitors (NRTIs). Therefore, the concomitant use of zidovudine or abacavir with 
Aptivus, co-administered with low dose ritonavir, is not-recommended unless there are no other 
available NRTIs suitable for patient management (see section 4.5).

Protease inhibitors
Concomitant use of Aptivus, co-administered with low dose ritonavir, with the protease inhibitors 
amprenavir, lopinavir or saquinavir (each co-administered with low dose ritonavir) in a dual-boosted 
regimen, results in significant decreases in plasma concentrations of these protease inhibitors. A 
significant decrease in plasma concentrations of atazanavir and a marked increase of tipranavir and 
ritonavir concentrations was observed when Aptivus, associated with low dose ritonavir, was co-
administered with atazanavir (see section 4.5). No data are currently available on interactions of 
tipranavir, co-administered with low dose ritonavir, with protease inhibitors other than those listed 
above. Therefore, the co-administration of tipranavir, co-administered with low dose ritonavir, with 
protease inhibitors is not recommended.

Oral contraceptives and oestrogens 
Since levels of ethinyl oestradiol are decreased, the co-administration of Aptivus co-administered with 
low dose ritonavir is not recommended. Alternative or additional contraceptive measures are to be 
used when oestrogen based oral contraceptives are co-administered with Aptivus co-administered with 
low dose ritonavir (see section 4.5). Patients using oestrogens as hormone replacement therapy should 
be clinically monitored for signs of oestrogen deficiency. Women using oestrogens may have an 
increased risk of non serious rash.

Anticonvulsants
Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin. Aptivus may 
be less effective due to decreased tipranavir plasma concentrations in patients taking these agents 
concomitantly (see section 4.5).

Halofantrine, lumefantrine
Due to their metabolic profile and inherent risk of inducing torsades de pointes, administration of 
halofantrine and lumefantrine with Aptivus co-administered with low dose ritonavir, is not 
recommended (see section 4.5).



43

Fluticasone
Concomitant use of tipranavir, co-administered with low dose ritonavir, and fluticasone or other 
glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of 
treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and 
adrenal suppression (see section 4.5).

Atorvastatin
Tipranavir, co-administered with low dose ritonavir, increases the plasma concentrations of 
atorvastatin (see section 4.5). The combination is not recommended. Other HMG-CoA reductase 
inhibitors should be considered such as pravastatin, fluvastatin or rosuvastatin (see section 4.5). 
However, if atorvastatin is specifically required for patient management, it should be started with the 
lowest dose and careful monitoring is necessary.

Omeprazole and other proton pump inhibitors
The combined use of Aptivus with ritonavir with either omeprazole, esomeprazole or with other 
proton pump inhibitors is not recommended (see section 4.5).  

Colchicine 
In patients with normal renal and hepatic function, a reduction in colchicine dosage or an interruption 
of colchicine treatment is recommended in co-administration (see section 4.5).

Salmeterol
Concomitant use of salmeterol and Aptivus, co-administered with low dose ritonavir, is not 
recommended (see section 4.5).

Bosentan
Due to the marked hepatotoxicity of bosentan and the potential for increasing the liver toxicity 
associated with Aptivus,co-administered with low dose ritonavir, this combination is not 
recommended.

4.5 Interaction with other medicinal products and other forms of interaction

The interaction profile of Aptivus, co-administered with low dose ritonavir, is complex and requires 
special attention in particular in combination with other antiretroviral agents.

Interaction studies have only been performed in adults.

Metabolic profile of tipranavir
Tipranavir is a substrate, an inducer and an inhibitor of cytochrome P450 CYP3A. When co-
administered with ritonavir at the recommended dosage (see section 4.2) there is a net inhibition of 
P450 CYP3A. Co-administration of Aptivus and low dose ritonavir with agents primarily metabolised 
by CYP3A may result in changed plasma concentrations of tipranavir or the other agents, which could 
alter their therapeutic and undesirable effects (see list and details of considered agents, below). Agents 
that are contraindicated specifically due to the expected magnitude of interaction and potential for 
serious adverse reactions are detailed in this section, and listed in section 4.3.

A cocktail study was conducted in 16 healthy volunteers with twice-daily tipranavir 500 mg with 
ritonavir 200 mg capsule administration for 10 days to assess the net effect on the activity of hepatic 
CYP 1A2 (caffeine), 2C9 (warfarin), 2D6 (dextromethorphan), both intestinal/hepatic CYP 3A4 
(midazolam) and P-glycoprotein (P-gp) (digoxin). At steady state, there was a significant induction of 
CYP 1A2 and a slight induction on CYP 2C9. Potent inhibition of CYP 2D6 and both hepatic and 
intestinal CYP 3A4 activities were observed. P-gp activity is significantly inhibited after the first dose, 
but there was a slight induction at steady state. Practical recommendations deriving from this study are 
displayed below. This study was also conducted with Aptivus oral solution 500 mg with ritonavir 
200 mg and showed the same CYP P450 and P-gp interactions as the Aptivus capsule 500 mg  with 
ritonavir 200 mg. Based on the results from this study, Aptivus oral solution might be expected to 
have a similar interaction profile as the capsules.



44

Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP 
2C19 and CYP 2D6. The potential net effect of tipranavir with ritonavir on CYP 2D6 is inhibition, 
because ritonavir is also a CYP 2D6 inhibitor. The in vivo net effect of tipranavir with ritonavir on 
CYP 1A2, CYP 2C9 and CYP 2C19, indicates, through a preliminary study, an inducing potential of 
tipranavir with ritonavir on CYP1A2 and, to a lesser extent, on CYP2C9 and P-gp after several days of 
treatment. Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl 
transferases. 

In vitro studies show that tipranavir is a substrate and also an inhibitor of P-gp. 

It is difficult to predict the net effect of Aptivus co-administered with low dose ritonavir on oral 
bioavailability and plasma concentrations of agents that are dual substrates of CYP3A and P-gp. The 
net effect will vary depending on the relative affinity of the co-administered substance for CYP3A and 
P-gp, and the extent of intestinal first-pass metabolism/efflux.

Co-administration of Aptivus and agents that induce CYP3A and/or P-gp may decrease tipranavir 
concentrations and reduce its therapeutic effect (see list and details of considered agents, below). Co-
administration of Aptivus and medicinal products that inhibit P-gp may increase tipranavir plasma 
concentrations.

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal 
products are listed in the table below.

Interaction table
Interactions between Aptivus and co-administered medicinal products are listed in the table below 
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”,once daily as “QD”, twice daily as 
“BID”, concentration at end of dosing interval as “Cτ”).
Unless otherwise stated, studies detailed below have been performed with the recommended dosage of 
Aptivus/r (i.e. 500/200 mg BID). However, some PK interaction studies were not performed with this 
recommended dosage. Nevertheless, the results of many of these interaction studies can be 
extrapolated to the recommended dosage since the doses used (eg. TPV/r 500/100 mg, TPV/r 
750/200 mg) represented extremes of hepatic enzyme induction and inhibition and bracketed the 
recommended dosage of Aptivus/r.

Drugs by Therapeutic Area Interaction
Geometric mean change (%)

Recommendations concerning
co-administration

Anti-infectives
Antiretrovirals
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
Since there is no significant impact of nucleoside and nucleotide analogues on the P450 enzyme system no 
dosage adjustment of Aptivus is required when co-administered with these agents.

Abacavir 300 mg BID
(TPV/r 750/100 mg BID)

Abacavir Cmax ↓ 46%
Abacavir AUC ↓ 36%

The clinical relevance of this 
reduction has not been 
established, but may decrease the 
efficacy of abacavir.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with abacavir is not 
recommended unless there are no 
other available NRTIs suitable for 
patient management. In such cases 
no dosage adjustment of abacavir 
can be recommended (see section 
4.4).

Didanosine 200 mg BID, ≥  
60 kg (TPV/r 250/200 mg 
BID) - 125 mg BID, < 60 kg
(TPV/r 750/100 mg BID)

Didanosine Cmax ↓ 43%
Didanosine AUC ↓ 33%

Dosing of enteric-coated didanosine 
and Aptivus soft capsules, co-
administered with low dose 
ritonavir, should be separated by at 



45

Didanosine Cmax ↓ 24%
Didanosine AUC ↔ 

The clinical relevance of this 
reduction in didanosine 
concentrations has not been
established.

Mechanism unknown.

least 2 hours to avoid formulation 
incompatibility.

Emtricitabine
No interaction study 
performed

Potential interactions with renal 
transporters cannot be fully 
excluded.

No dosage adjustment necessary in 
patients with normal renal function.
In case of concomitant 
administration of emtricitabine and 
Aptivus/ritonavir, renal function 
should be evaluated before initiating 
the co-administration.

Lamivudine 150 mg BID
(TPV/r 750/100 mg BID)

No clinically significant 
interaction is observed.

No dosage adjustment necessary.

Stavudine
40 mg BID > 60 kg
30 mg BID < 60 kg
(TPV/r 750/100 mg BID)

No clinically significant 
interaction is observed.

No dosage adjustment necessary.

Zidovudine 300 mg BID
(TPV/r 750/100 mg BID)

Zidovudine Cmax ↓ 49%
Zidovudine AUC ↓ 36%

The clinical relevance of this 
reduction has not been 
established, but may decrease the 
efficacy of zidovudine.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir with zidovudine is not 
recommended unless there are no 
other available NRTIs suitable for 
patient management. In such cases 
no dosage adjustment of zidovudine 
can be recommended (see section 
4.4). 

Tenofovir  300 mg QD 
(TPV/r 750/200 mg BID)

No clinically significant 
interaction is observed.

No dosage adjustment necessary.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg QD No clinically significant interaction 

is observed.
No dosage adjustment necessary.

Etravirine Etravirine Cmax ↓ 71%
Etravirine AUC ↓ 76%
Etravirine Cmin ↓ 82%

Concomitant use of 
Aptivus/ritonavir caused a decrease 
of etravirine exposure that could 
significantly impair the virologic 
response to etravirine. 

Co-administration of etravirine and 
Aptivus/ritonavir is not 
recommended.

Nevirapine
No interaction study 
performed

The limited data available from a 
phase IIa study in HIV-infected 
patients suggest that no significant 
interaction is expected between 
nevirapine and TPV/r. Moreover a 
study with TPV/r and another
NNRTI (efavirenz) did not show 
any clinically relevant interaction 
(see above).

No dosage adjustment necessary.

Rilpivirine
No interaction study 
performed

Concomitant use of rilpivirine with 
some ritonavir-boosted protease 
inhibitors has demonstrated an 

Close monitoring for signs of 
rilpivirine toxicity and possibly also 
dose adjustment of rilpivirine is 



46

increase in the plasma 
concentrations of rilpivirine.

recommended when co-
administered with Aptivus/ritonavir.

Protease inhibitors (PIs)
According to current treatment guidelines, dual therapy with protease inhibitors is generally not 
recommended
Amprenavir/ritonavir 
600/100 mg BID

Amprenavir Cmax ↓ 39% 
Amprenavir AUC ↓ 44% 
Amprenavir Cmin ↓ 55%

The clinical relevance of this 
reduction in amprenavir 
concentrations has not been 
established.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with amprenavir/ritonavir 
is not recommended.
If the combination is nevertheless 
considered necessary, a monitoring 
of the plasma levels of amprenavir 
is strongly encouraged (see section 
4.4).

Atazanavir/ritonavir
300/100 mg QD
(TPV/r 500/100 mg BID)

Atazanavir Cmax ↓ 57% 
Atazanavir AUC ↓ 68% 
Atazanavir Cmin ↓ 81% 

Mechanism unknown.

Tipranavir Cmax  8% 
Tipranavir AUC  20% 
Tipranavir Cmin  75%

Inhibition of CYP 3A4 by 
atazanavir/ritonavir and induction 
by tipranavir/r.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with atazanavir/ritonavir 
is not recommended.
If the co-administration is 
nevertheless considered necessary, a 
close monitoring of the safety of 
tipranavir and a monitoring of 
plasma concentrations of atazanavir 
are strongly encouraged (see section 
4.4).

Lopinavir/ritonavir
400/100 mg BID

Lopinavir Cmax ↓ 47%
Lopinavir AUC ↓ 55% 
Lopinavir Cmin ↓ 70%

The clinical relevance of this 
reduction in lopinavir 
concentrations has not been 
established.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with lopinavir/ritonavir is 
not recommended.
If the combination is nevertheless 
considered necessary, a monitoring 
of the plasma levels of lopinavir is 
strongly encouraged (see section 
4.4). 

Saquinavir/ritonavir
600/100 mg QD

Saquinavir Cmax ↓ 70%
Saquinavir AUC ↓ 76% 
Saquinavir Cmin ↓ 82% 

The clinical relevance of this 
reduction in saquinavir 
concentrations has not been 
established.

Mechanism unknown.

The concomitant use of Aptivus, co-
administered with low dose 
ritonavir, with saquinavir/ritonavir 
is not recommended.
If the combination is nevertheless 
considered necessary, a monitoring 
of the plasma levels of saquinavir is 
strongly encouraged (see section 
4.4). 

Protease inhibitors other 
than those listed above

No data are currently available on 
interactions of tipranavir, co-
administered with low dose 
ritonavir, with protease inhibitors 
other than those listed above.

Combination with Aptivus, co-
administered with low dose 
ritonavir, is not recommended (see 
section 4.4)

Fusion inhibitors
Enfuvirtide 
No interaction study 

In studies where tipranavir co-
administered with low-dose 

The clinical impact of the observed 
data, especially regarding the 



47

performed ritonavir was used with or without 
enfuvirtide, it has been observed 
that the steady-state plasma 
tipranavir trough concentration of 
patients receiving enfuvirtide were 
45% higher as compared to patients 
not receiving enfuvirtide. No 
information is available for the 
parameters AUC and Cmax. 
A pharmacokinetic interaction is 
mechanistically unexpected and the 
interaction has not been confirmed 
in a controlled interaction study.

tipranavir with ritonavir safety 
profile, remains unknown. 
Nevertheless, the clinical data 
available from the RESIST trials did 
not suggest any significant 
alteration of the tipranavir with 
ritonavir safety profile when 
combined with enfuvirtide as 
compared to patients treated with 
tipranavir with ritonavir without 
enfuvirtide.

Integrase strand transfer inhibitors
Raltegravir 400 mg BID Raltegravir Cmax ↔

Raltegravir AUC 0-12↔
Raltegravir C12: ↓ 45%

Despite an almost half reduction of 
C12, previous clinical studies with 
this combination did not evidence 
an impaired outcome. 

The mechanism of action is thought 
to be induction of 
glucuronosyltransferase by 
tipranavir/r.

No particular dose adjustment is 
recommended when
Aptivus/ritonavir is administered
with Raltegravir 400 mg BID.
For other doses of raltegravir,
please refer to the relevant product
information for raltegravir.

Dolutegravir 50 mg QD Dolutegravir ↓
AUC ↓ 59%
Cmax ↓ 47%
Cτ ↓ 76%
(induction of UGT1A1 and
CYP3A enzymes) 

In paediatric patients the weight-
based once daily dose should be
administered twice daily. In the 
presence of integrase class 
resistance this combination should 
be avoided (see dolutegravir 
SmPC).

Pharmacokinetic enhancer
Cobicistat and cobicistat-
containing products

When co-administered, tipranavir 
and cobicistat exposures are 
markedly lower compared to that of 
tipranavir when boosted with low 
dose ritonavir.   

Aptivus/ritonavir should not be 
administered concomitantly with 
cobicistat or cobicistat-containing 
products.

Anti-HCV agents
Boceprevir
No interaction study 
performed

In a pharmacokinetic study of 
healthy volunteers, boceprevir 
decreased the exposure of ritonavir, 
and some ritonavir-boosted protease 
inhibitors. Boceprevir exposure was 
reduced when co-administered with 
ritonavir-boosted lopinavir or 
ritonavir-boosted darunavir. These 
drug-drug interactions may reduce 
the effectiveness of HIV protease 
inhibitors and/or boceprevir when 
co-administered. 

Co-administration of boceprevir 
with Aptivus/ritonavir is not 
recommended.

Telaprevir
No interaction study 
performed

Telaprevir is metabolized in the 
liver by CYP3A and is a P-
glycoprotein (P-gp) substrate, but 

Co-administration of telaprevir with 
Aptivus/ritonavir is not 
recommended.



48

other enzymes may be involved in 
the metabolism. When
Aptivus/ritonavir is co-administered 
with telaprevir, a decrease or an 
increase of telaprevir exposure 
could be expected. There is a 
heterogeneous effect of telaprevir 
on ritonavir-boosted protease 
inhibitor drug plasma levels, 
depending on the protease 
inhibitors. Therefore, a 
modification of Aptivus exposure 
cannot be ruled out.

Antifungals
Fluconazole 200 mg QD 
(Day 1) then 100 mg QD

Fluconazole ↔

Tipranavir Cmax ↑ 32% 
Tipranavir AUC ↑ 50% 
Tipranavir Cmin ↑ 69% 

Mechanism unknown

No dosage adjustments are 
recommended. Fluconazole doses 
200 mg/day are not recommended.

Itraconazole
Ketoconazole
No interaction study 
performed

Based on theoretical considerations 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase itraconazole or 
ketoconazole concentrations.

Based on theoretical considerations, 
tipranavir or ritonavir 
concentrations might increase upon 
co-administration with itraconazole 
or ketoconazole.

Itraconazole or ketoconazole should 
be used with caution (doses 
200 mg/day are not 
recommended).

Voriconazole
No interaction study 
performed

Due to multiple CYP isoenzyme 
systems involved in voriconazole 
metabolism, it is difficult to predict 
the interaction with tipranavir, co-
administered with low-dose 
ritonavir.

Based on the known interaction of 
voriconazole with low dose 
ritonavir (see voriconazole SmPC) 
the co-administration of tipranavir/r 
and voriconazole should be 
avoided, unless an assessment of 
the benefit/risk to the patient 
justifies the use of voriconazole.

Anti-gouts
Colchicine
No interaction study 
performed

Based on theoretical considerations, 
colchicine concentrations may 
increase upon co-administration 
with tipranavir and low dose 
ritonavir, due to tipranavir/ritonavir 
CYP3A and P-gp inhibition. 
However a decrease of colchicine 
concentrations cannot be excluded 
since both tipranavir and ritonavir 
exhibit inducing potential towards
CYP3A and P-gp.

Colchicine is a substrate of 
CYP3A4 and P-gp (an intestinal 
efflux transporter).

A reduction in colchicine dosage or 
an interruption of colchicine 
treatment is recommended in 
patients with normal renal or 
hepatic function if treatment with 
Aptivus/ritonavir is required (see 
section 4.4). In patients with renal 
or hepatic impairment, co-
administration of colchicine in 
patients on Aptivus/ritonavir is 
contraindicated (see section 4.3).



49

Antibiotics
Clarithromycin 500 mg 
BID

Clarithromycin Cmax ↔
Clarithromycin AUC ↑ 19% 
Clarithromycin Cmin ↑ 68%

14-OH-clarithromycin Cmax ↓ 97%
14-OH-clarithromycin AUC ↓ 97% 
14-OH-clarithromycin Cmin ↓ 95% 

Tipranavir Cmax ↑ 40%
Tipranavir AUC ↑ 66% 
Tipranavir Cmin ↑ 100%

CYP 3A4 inhibition by tipranavir/r
and P-gp (an intestinal efflux 
transporter) inhibition by 
clarithromycin.

Whilst the changes in 
clarithromycin parameters are not 
considered clinically relevant, the 
reduction in the 14-OH metabolite 
AUC should be considered for the 
treatment of infections caused by 
Haemophilus influenzae in which 
the 14-OH metabolite is most 
active. The increase of tipranavir 
Cmin may be clinically relevant. 
Patients using clarithromycin at 
doses higher than 500 mg twice 
daily should be carefully monitored 
for signs of toxicity of 
clarithromycin and tipranavir. For 
patients with renal impairment dose 
reduction of clarithromycin should 
be considered (see clarithromycin 
and ritonavir product information).

Rifabutin 150 mg QD Rifabutin Cmax ↑ 70%
Rifabutin AUC ↑ 190% 
Rifabutin Cmin ↑ 114% 

25-O-desacetylrifabutin Cmax ↑ 3.2 
fold
25-O-desacetylrifabutin AUC ↑ 21 
fold
25-O-desacetylrifabutin Cmin ↑ 7.8 
fold 

Inhibition of CYP 3A4 by 
tipranavir/r

No clinically significant change is 
observed in tipranavir PK 
parameters.

Dosage reductions of rifabutin by at 
least 75% of the usual 300 mg/day 
are recommended (ie 150 mg on 
alternate days, or three times per 
week). Patients receiving rifabutin 
with Aptivus, co-administered with 
low dose ritonavir, should be 
closely monitored for emergence of 
adverse events associated with 
rifabutin therapy. Further dosage 
reduction may be necessary.

Rifampicin Co-administration of protease 
inhibitors with rifampicin 
substantially decreases protease 
inhibitor concentrations. In the case 
of tipranavir co-administered with 
low dose ritonavir, concomitant use 
with rifampicin is expected to result 
in sub-optimal levels of tipranavir 
which may lead to loss of virologic 
response and possible resistance to 
tipranavir.

Concomitant use of Aptivus, co-
administered with low dose 
ritonavir, and rifampicin is 
contraindicated (see section 4.3). 
Alternate antimycobacterial agents 
such as rifabutin should be 
considered.

Antimalarial
Halofantrine
Lumefantrine 
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase halofantrine and 
lumefantrine concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

Due to their metabolic profile and 
inherent risk of inducing torsades 
de pointes, administration of 
halofantrine and lumefantrine with 
Aptivus, co-administered with low 
dose ritonavir, is not recommended 
(see section 4.4).



50

Anticonvulsants
Carbamazepine 200 mg 
BID

Carbamazepine total* Cmax ↑ 13%
Carbamazepine total* AUC ↑ 16% 
Carbamazepine total* Cmin ↑ 23%

*Carbamazepine total = total of 
carbamazepine and epoxy-
carbamazepine (both are 
pharmacologically active moieties).

The increase in carbamazepine total 
PK parameters is not expected to 
have clinical consequences.

Tipranavir Cmin ↓ 61% (compared to 
historical data)

The decrease in tipranavir 
concentrations may result in 
decreased effectiveness.

Carbamazepine induces CYP3A4.

Carbamazepine should be used with 
caution in combination with 
Aptivus, co-administered with low 
dose ritonavir. Higher doses of 
carbamazepine (> 200 mg) may 
result in even larger decreases in 
tipranavir plasma concentrations 
(see section 4.4). 

Phenobarbital
Phenytoin
No interaction study 
performed

Phenobarbital and phenytoin induce 
CYP3A4.

Phenobarbital and phenytoin should 
be used with caution in combination 
with Aptivus, co-administered with 
low dose ritonavir (see section 4.4).

Antispasmodic
Tolterodine
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase tolterodine concentrations.

Inhibition of CYP 3A4 and CYP 
2D6 by tipranavir/r

Co-administration is not 
recommended.

Endothelin receptor antagonists
Bosentan Based on theoretical considerations, 

bosentan concentrations may 
increase upon co-administration 
with tipranavir and low dose 
ritonavir.

Inhibition of CYP 3A4 by 
tipranavir/r 

Co-administration of bosentan and 
Aptivus with low dose ritonavir is 
not recommended
(see section 4.4).

HMG CoA reductase inhibitors
Atorvastatin 10 mg QD Atorvastatin Cmax ↑ 8.6 fold 

Atorvastatin AUC ↑ 9.4 fold 
Atorvastatin Cmin ↑ 5.2 fold 

Tipranavir ↔

Inhibition of CYP 3A4 by 
tipranavir/r

Co-administration of atorvastatin 
and Aptivus, co-administered with 
low dose ritonavir, is not 
recommended. Other HMG-CoA 
reductase inhibitors should be 
considered such as pravastatin, 
fluvastatin or rosuvastatin (See also 
section 4.4 and rosuvastatin and 
pravastatin recommendations). In 
cases where co-administration is 
necessary, the dose of 10 mg 
atorvastatin daily should not be 
exceeded. It is recommended to 



51

start with the lowest dose and 
careful clinical monitoring is 
necessary (see section 4.4).

Rosuvastatin  10 mg QD Rosuvastatin Cmax ↑ 123% 
Rosuvastatin AUC ↑ 37% 
Rosuvastatin Cmin ↑ 6% 

Tipranavir ↔

Mechanism unknown.

Co-administration of Aptivus, co-
administered with low dose 
ritonavir, and rosuvastatin should 
be initiated with the lowest dose 
(5 mg/day) of rosuvastatin, titrated 
to treatment response, and 
accompanied with careful clinical 
monitoring for rosuvastatin 
associated symptoms as described 
in the label of rosuvastatin.  

Pravastatin
No interaction study 
performed

Based on similarities in the 
elimination between pravastatin and 
rosuvastatin, TPV/r could increase 
the plasma levels of pravastatin. 

Mechanism unknown.

Co-administration of Aptivus, co-
administered with low dose 
ritonavir, and pravastatin should be 
initiated with the lowest dose 
(10 mg/day) of pravastatin, titrated 
to treatment response, and 
accompanied with careful clinical 
monitoring for pravastatin 
associated symptoms as described 
in the label of pravastatin.

Simvastatin
Lovastatin
No interaction study 
performed

The HMG-CoA reductase inhibitors 
simvastatin and lovastatin are 
highly dependent on CYP3A for 
metabolism.

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with simvastatin or 
lovastatin are contra-indicated due 
to an increased risk of myopathy, 
including rhabdomyolysis (see
section 4.3).

HERBAL PRODUCTS
St. John’s wort (Hypericum 
perforatum)
No interaction study 
performed

Plasma concentrations of tipranavir 
can be reduced by concomitant use 
of the herbal preparation St John’s 
wort (Hypericum perforatum). This 
is due to induction of drug 
metabolising enzymes by St John’s 
wort.

Herbal preparations containing St. 
John’s wort must not be combined 
with Aptivus, co-administered with 
low dose ritonavir. Co-
administration of Aptivus with 
ritonavir, with St. John’s wort is 
expected to substantially decrease 
tipranavir and ritonavir 
concentrations and may result in 
sub-optimal levels of tipranavir and 
lead to loss of virologic response 
and possible resistance to 
tipranavir.

Inhaled beta agonists
Salmeterol The concurrent administration of 

tipranavir and low dose ritonavir
may result in increased risk of 
cardiovascular adverse events 
associated with salmeterol, 
including QT prolongation, 
palpitations and sinus tachycardia.

Inhibition of CYP 3A4 by 
tipranavir/r.

Concurrent administration of 
Aptivus, co-administered with low 
dose ritonavir, is not recommended.



52

Oral contraceptives / Oestrogens
Ethinyl oestradiol 0.035 mg 
/ Norethindrone 1.0 mg QD
(TPV/r 750/200 mg BID)

Ethinyl oestradiol Cmax ↓ 52% 
Ethinyl oestradiol AUC ↓ 43% 

Mechanism unknown

Norethindrone Cmax ↔ 
Norethindrone AUC ↑ 27% 

Tipranavir ↔

The concomitant administration 
with Aptivus, co-administered with 
low dose ritonavir, is not 
recommended. Alternative or 
additional contraceptive measures 
are to be used when oestrogen 
based oral contraceptives are co-
administered with Aptivus and low 
dose ritonavir. Patients using 
oestrogens as hormone replacement 
therapy should be clinically 
monitored for signs of oestrogen 
deficiency (see sections 4.4 and 
4.6).

Phosphodiesterase 5 (PDE5) inhibitors
Sildenafil
Vardenafil
No interaction study 
performed

Co-administration of tipranavir and 
low dose ritonavir with PDE5 
inhibitors is expected to 
substantially increase PDE5 
concentrations and may result in an 
increase in PDE5 inhibitor-
associated adverse events including 
hypotension, visual changes and 
priapism.

CYP 3A4 inhibition by tipranavir/ r

Particular caution should be used 
when prescribing the 
phosphodiesterase (PDE5) 
inhibitors sildenafil or vardenafil in 
patients receiving Aptivus, co-
administered with low dose 
ritonavir.
A safe and effective dose has not 
been established when used with 
Aptivus, co-administered with low 
dose ritonavir. There is increased 
potential for PDE5 inhibitor-
associated adverse events (which 
include visual disturbances, 
hypotension, prolonged erection, 
and syncope).
Co-administration of 
Aptivus/ritonavir with sildenafil, 
when used to treat pulmonary 
arterial hypertension, is 
contraindicated.

Tadalafil 10 mg QD Tadalafil first-dose Cmax ↓ 22%
Tadalafil first-dose AUC ↑ 133% 

CYP 3A4 inhibition and induction 
by tipranavir/r

Tadalafil steady-state Cmax ↓ 30%
Tadalafil steady-state AUC ↔ 

No clinically significant change is 
observed in tipranavir PK 
parameters.

It is recommended to prescribe 
tadalafil after at least 7 days of 
Aptivus with ritonavir dosing.
A safe and effective dose has not 
been established when used with 
Aptivus, co-administered with low 
dose ritonavir. There is increased 
potential for PDE5 inhibitor-
associated adverse events (which 
include visual disturbances, 
hypotension, prolonged erection, 
and syncope).

Narcotic analgesics
Methadone 5 mg QD Methadone Cmax ↓ 55% 

Methadone AUC ↓ 53% 
Methadone Cmin ↓ 50% 

R-methadone Cmax ↓ 46% 
R-methadone AUC ↓ 48%

Patients should be monitored for 
opiate withdrawal syndrome. 
Dosage of methadone may need to 
be increased.



53

S-methadone Cmax ↓ 62% 
S-methadone AUC ↓ 63% 

Mechanism unknown
Meperidine
No interaction study 
performed

Tipranavir, co-administered with 
low dose ritonavir, is expected to 
decrease meperidine concentrations 
and increase normeperidine 
metabolite concentrations.

Dosage increase and long-term use 
of meperidine with Aptivus, co-
administered with low dose 
ritonavir, are not recommended due 
to the increased concentrations of 
the metabolite normeperidine which 
has both analgesic activity and CNS 
stimulant activity (e.g. seizures).

Buprenorphine/Naloxone Buprenorphine ↔ 

Norbuprenorphine AUC  79%
Norbuprenorphine Cmax  80% 
Norbuprenorphine Cmin  80% 

Due to reduction in the levels of the 
active metabolite norbuprenorphine, 
co-administration of Aptivus, co-
administered with low dose 
ritonavir, and 
buprenorphine/naloxone may result 
in decreased clinical efficacy of 
buprenorphine. Therefore, patients 
should be monitored for opiate 
withdrawal syndrome.

Immunosupressants
Cyclosporin
Tacrolimus
Sirolimus
No interaction study 
performed

Concentrations of cyclosporin, 
tacrolimus, or sirolimus cannot be 
predicted when co-administered 
with tipranavir co-administered 
with low dose ritonavir, due to 
conflicting effect of tipranavir, co-
administered with low dose 
ritonavir, on CYP 3A and P-gp.

More frequent concentration 
monitoring of these medicinal 
products is recommended until 
blood levels have been stabilised.

Antithrombotics
Warfarin 10 mg QD First-dose tipranavir /r:

S-warfarin Cmax ↔
S-warfarin AUC ↑ 18% 

Steady-state tipranavir/r:
S-warfarin Cmax ↓ 17% 
S-warfarin AUC ↓ 12% 

Inhibition of CYP 2C9 with first-
dose tipranavir /r, then induction of 
CYP 2C9 with steady-state 
tipranavir/r

Aptivus, co-administered with low 
dose ritonavir, when combined with 
warfarin may be associated with 
changes in INR (International 
Normalised Ratio) values, and may 
affect anticoagulation 
(thrombogenic effect) or increase 
the risk of bleeding. Close clinical 
and biological (INR measurement) 
monitoring is recommended when 
warfarin and tipranavir are 
combined.

Antacids
aluminium- and magnesium-
based antacid QD 

Tipranavir Cmax ↓ 25%
Tipranavir AUC ↓ 27%

Mechanism unknown 

Dosing of Aptivus, co-administered 
with low dose ritonavir, with 
antacids should be separated by at 
least a two hours time interval. 

Proton pump inhibitors (PPIs)
Omeprazole 40 mg QD Omeprazole Cmax ↓ 73% 

Omeprazole AUC ↓ 70%

Similar effects were observed for 
the S-enantiomer, esomeprazole.  

The combined use of Aptivus, co-
administered with low dose 
ritonavir, with either omeprazole or 
esomeprazole is not recommended 
(see section 4.4). If unavoidable, 
upward dose adjustments for either 



54

Induction of CYP 2C19 by 
tipranavir/r

Tipranavir ↔

omeprazole or esomeprazole may 
be considered based on clinical 
response to therapy. There are no 
data available indicating that 
omeprazole or esomeprazole dose 
adjustments will overcome the 
observed pharmacokinetic 
interaction. Recommendations for 
maximal doses of omeprazole or 
esomeprazole are found in the 
corresponding product information. 
No tipranavir with ritonavir dose 
adjustment is required.

Lansoprazole
Pantoprazole
Rabeprazole
No interaction study 
performed

Based on the metabolic profiles of 
tipranavir/r and the proton pump 
inhibitors, an interaction can be 
expected. As a result of CYP3A4 
inhibition and CYP2C19 induction 
by tipranavir/r, lansoprazole and 
pantoprazole plasma concentrations 
are difficult to predict. Rabeprazole 
plasma concentrations might 
decrease as a result of induction of 
CYP2C19 by tipranavir/r.

The combined use of Aptivus, co-
administered with low dose 
ritonavir, with proton pump 
inhibitors is not recommended (see 
section 4.4). If the co-
administration is judged 
unavoidable, this should be done 
under close clinical monitoring.

H2-receptor antagonists
No interaction study 
performed

No data are available for H2-
receptor antagonists in combination 
with tipranavir and low dose 
ritonavir.

An increase in gastric pH that may 
result from H2-receptor antagonist 
therapy is not expected to have an 
impact on tipranavir plasma 
concentrations.  

Antiarrhythmics
Amiodarone
Bepridil
Quinidine
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase amiodarone, bepridil and 
quinidine concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with amiodarone, bepridil 
or quinidine is contraindicated due 
to potential serious and/or life 
threatening events (see section 4.3)

Flecainide
Propafenone 
Metoprolol (given in heart 
failure)
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase flecainide, propafenone 
and metoprolol concentrations.

Inhibition of CYP 2D6
by tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with flecainide, 
propafenone or metoprolol is 
contraindicated (see section 4.3)

Antihistamines
Astemizole
Terfenadine
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase astemizole and terfenadine 
concentrations.

Inhibition of CYP 3A4 by 

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with astemizole or 
terfenadine is contraindicated due to 
potential serious and/or life 
threatening events (see section 4.3)



55

tipranavir/r
Ergot derivatives

Dihydroergotamine
Ergonovine
Ergotamine 
Methylergonovine
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase dihydroergotamine, 
ergonovine, ergotamine and 
methylergonovine concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with dihydroergotamine, 
ergonovine, ergotamine or  
methylergonovine is 
contraindicated due to potential 
serious and/or life threatening 
events (see section 4.3)

Gastrointestinal motility agents
Cisapride
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase cisapride concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with cisapride is 
contraindicated due to potential 
serious and/or life threatening 
events (see section 4.3)

Antipsychotics
Pimozide
Sertindole
Quetiapine
Lurasidone
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase pimozide, sertindole,  
quetiapine and lurasidone 
concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with antipsychotics such 
as pimozide, sertindole, quetiapine
or lurasidone is contraindicated due 
to potential serious and/or life 
threatening events, including coma 
(see section 4.3)

Sedatives/hypnotics
Midazolam 2 mg QD (iv)

Midazolam 5 mg QD (po)

First-dose tipranavir/r:
Midazolam Cmax ↔ 
Midazolam AUC ↑ 5.1 fold 

Steady-state tipranavir/r:
Midazolam Cmax ↓ 13%
Midazolam AUC ↑ 181% 

First-dose tipranavir/r
Midazolam Cmax ↑ 5.0 fold 
Midazolam AUC ↑ 27 fold 

Steady-state tipranavir/r
Midazolam Cmax ↑ 3.7 fold 
Midazolam AUC ↑ 9.8 fold

Ritonavir is a potent inhibitor of 
CYP3A4 and therefore affect drugs 
metabolised by this enzyme.

Concomitant use of Aptivus, co-
administered with low dose 
ritonavir, and sedative/hypnotics 
such as oral midazolam is contra-
indicated (see section 4.3). If 
Aptivus with ritonavir is 
administered with parenteral 
midazolam, close clinical 
monitoring for respiratory 
depression and/or prolonged 
sedation should be instituted and 
dosage adjustment should be 
considered.

Triazolam
No interaction study 
performed

Based on theoretical considerations, 
tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase triazolam concentrations.

Inhibition of CYP 3A4 by 
tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with triazolam is 
contraindicated due to potential 
serious and/or life threatening 
events (see section 4.3)



56

Nucleoside analogue DNA polymerase inhibitors
Valaciclovir 500 mg single 
dose

Co-administration of valaciclovir, 
tipranavir and low dose ritonavir 
was not associated with clinically 
relevant pharmacokinetic effects.

Tipranavir: ↔
Valaciclovir: ↔

Valaciclovir and Aptivus with low 
dose of ritonavir may be co-
administered without dose 
adjustment.

Alpha 1-adrenoreceptor antagonists
Alfuzosin Based on theoretical considerations, 

co-administration of tipranavir with 
low dose ritonavir and alfuzosin 
results in increased alfuzosin 
concentrations and may result in 
hypotension.

CYP 3A4 inhibition by tipranavir/r

The concomitant use of Aptivus, 
co-administered with low dose 
ritonavir, with alfuzosin is 
contraindicated.

Others
Theophylline
No interaction study 
performed

Based on data from the cocktail 
study where caffeine (CYP1A2 
substrate) AUC was reduced by 
43%, tipranavir with ritonavir is 
expected to decrease theophylline 
concentrations.  

Induction of CYP 1A2 by 
tipranavir/r

Theophylline plasma concentrations 
should be monitored during the first 
two weeks of co-administration 
with Aptivus, co-administered with 
low dose ritonavir, and the 
theophylline dose should be 
increased as needed.

Desipramine
No interaction study 
performed

Tipranavir, co-administered with 
low dose ritonavir, is expected to 
increase desipramine concentrations

Inhibition of CYP 2D6 by 
tipranavir/r

Dosage reduction and concentration 
monitoring of desipramine is 
recommended.

Digoxin 0.25 mg QD iv 

Digoxin 0.25 mg QD po

First-dose tipranavir/r
Digoxin Cmax ↔ 
Digoxin AUC ↔ 

Steady-state tipranavir/r
Digoxin Cmax ↓ 20% 
Digoxin AUC ↔ 

First-dose tipranavir/r
Digoxin Cmax ↑ 93% 
Digoxin AUC ↑ 91%

Transient inhibition of P-gp by 
tipranavir/r, followed by induction 
of P-gp by tipranavir/r at steady-
state

Steady-state tipranavir/r
Digoxin Cmax ↓ 38% 
Digoxin AUC ↔ 

Monitoring of digoxin serum 
concentrations is recommended 
until steady state has been obtained.

Trazodone
Interaction study performed 
only with ritonavir

In a pharmacokinetic study 
performed in healthy volunteers, 
concomitant use of low dose 
ritonavir (200 mg twice daily) with 

The combination should be used 
with caution and a lower dose of 
trazodone should be considered.



57

a single dose of trazodone led to an 
increased plasma concentration of 
trazodone (AUC increased by 
2.4 fold). Adverse events of nausea, 
dizziness, hypotension and syncope 
have been observed following co-
administration of trazodone and 
ritonavir in this study. However, it 
is unknown whether the 
combination of tipranavir with 
ritonavir might cause a larger 
increase in trazodone exposure.

Bupropion 150 mg BID Bupropion Cmax ↓ 51% 
Bupropion AUC ↓ 56%

Tipranavir ↔

The reduction of bupropion plasma 
levels is likely due to induction of 
CYP2B6 and UGT activity by RTV

If the co-administration with 
bupropion is judged unavoidable, 
this should be done under close 
clinical monitoring for bupropion 
efficacy, without exceeding the 
recommended dosage, despite the 
observed induction.

Loperamide 16 mg QD Loperamide Cmax ↓ 61% 
Loperamide AUC ↓ 51% 

Mechanism unknown

Tipranavir Cmax ↔ 
Tipranavir AUC ↔ 
Tipranavir Cmin ↓ 26% 

A pharmacodynamic interaction 
study in healthy volunteers 
demonstrated that administration of 
loperamide and Aptivus, co-
administered with low dose 
ritonavir, does not cause any 
clinically relevant change in the 
respiratory response to carbon 
dioxide. The clinical relevance of 
the reduced loperamide plasma 
concentration is unknown. 

Fluticasone propionate
Interaction study performed 
only with ritonavir

In a clinical study where ritonavir 
100 mg capsules bid were co-
administered with 50 µg intranasal 
fluticasone propionate (4 times 
daily) for 7 days in healthy subjects, 
the fluticasone propionate plasma 
levels increased significantly, 
whereas the intrinsic cortisol levels 
decreased by approximately 86% 
(90% confidence interval 82-89%). 
Greater effects may be expected 
when fluticasone propionate is 
inhaled. Systemic corticosteroid 
effects including Cushing's 
syndrome and adrenal suppression 
have been reported in patients 
receiving ritonavir and inhaled or 
intranasally administered 
fluticasone propionate; this could 
also occur with other corticosteroids
metabolised via the P450 3A 
pathway e.g. budesonide. 
It is unknown whether the 
combination of tipranavir with 
ritonavir might cause a larger 
increase in fluticasone exposure.

Concomitant administration of 
Aptivus, co-administered with low 
dose ritonavir, and these 
glucocorticoids is not recommended 
unless the potential benefit of 
treatment outweighs the risk of 
systemic corticosteroid effects (see 
section 4.4). A dose reduction of the 
glucocorticoid should be considered 
with close monitoring of local and 
systemic effects or a switch to a 
glucocorticoid, which is not a 
substrate for CYP3A4 (e.g. 
beclomethasone). Moreover, in case 
of withdrawal of glucocorticoids 
progressive dose reduction may 
have to be performed over a longer 
period. The effects of high 
fluticasone systemic exposure on 
ritonavir plasma levels are as yet 
unknown.



58

4.6 Fertility, pregnancy and lactation

Contraception in males and females
Tipranavir adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe 
method of contraception should be used during treatment (see section 4.5).

Pregnancy
There are no adequate data from the use of tipranavir in pregnant women. Studies in animals have 
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Tipranavir 
should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breastfeeding
Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants 
under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue 
breast-feeding if they are receiving Aptivus.

Fertility
Clinical data on fertility are not available for tipranavir. Preclinical studies performed with tipranavir 
showed no adverse effect on fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Dizziness, somnolence, and fatigue have been reported in some patients; therefore, caution should be 
recommended when driving a car or operating machinery. If patients experience fatigue, dizziness, or 
somnolence they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable effects

Summary of the safety profile
Amongst the most common adverse reactions reported for Aptivus were gastrointestinal complaints 
such as diarrhoea and nausea as well as hyperlipidaemia. The most serious adverse reactions include 
hepatic impairment and liver toxicity. Intracranial haemorrhage (ICH) was only observed in post 
marketing experience (see section 4.4).

Aptivus co-administered with low dose ritonavir, has been associated with reports of significant liver 
toxicity. In Phase III RESIST trials, the frequency of transaminase elevations was significantly 
increased in the tipranavir with ritonavir arm compared to the comparator arm. Close monitoring is 
therefore needed in patients treated with Aptivus, co-administered with low dose ritonavir (see section 
4.4).

Limited data are currently available for the use of Aptivus, co-administered with low dose ritonavir, in 
patients co-infected with hepatitis B or C. Aptivus should therefore be used with caution in patients 
co-infected with hepatitis B or C. Aptivus should be used in this patient population only if the 
potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring.

Tabulated summary of adverse reactions
Assessment of adverse reactions from HIV-1 clinical study data is based on experience in all Phase II 
and III trials in adults treated with the 500 mg tipranavir with 200 mg ritonavir dose twice daily 
(n=1397) and are listed below by system organ class and frequency according to the following 
categories:
Very common (≥ 1/10), common (≥ 1/100 to 1/10), uncommon (≥1/1,000 to 1/100), 
rare (≥1/10,000 to 1/1,000) 

Tabulated summary of adverse reactions associated with Aptivus based on clinical studies and post-
marketing experience:



59

Blood and lymphatic 
system disorders
uncommon neutropenia, anaemia, thrombocytopenia
Immune system disorders

uncommon hypersensitivity
Metabolism and nutrition disorders

common hypertriglyceridaemia, hyperlipidaemia
uncommon anorexia, decreased appetite, weight decreased, 

hyperamylasaemia, hypercholesterolaemia, 
diabetes mellitus, hyperglycaemia

rare dehydration

Psychiatric disorders

uncommon insomnia, sleep disorder

Nervous system disorders

common headache

uncommon dizziness, neuropathy peripheral, somnolence

rare intracranial haemorrhage*

Respiratory, thoracic and 
mediastinal disorders
uncommon dyspnoea

Gastrointestinal disorders

very common diarrhoea, nausea

common vomiting, flatulence, abdominal pain, abdominal 
distension, dyspepsia

uncommon gastrooesophageal reflux disease, pancreatitis

rare lipase increased

Hepatobiliary disorders

uncommon hepatic enzyme increased (ALAT, ASAT), 
cytolytic hepatitis, liver function test abnormal 
(ALAT, ASAT), hepatitis toxic

rare hepatic failure (including fatal outcome), 
hepatitis, hepatic steatosis, hyperbilirubinaemia

Skin and subcutaneous tissue disorders

common rash

uncommon pruritus, exanthem

Musculoskeletal and connective 
tissue disorders
uncommon myalgia, muscle spasms

Renal and urinary disorders

uncommon renal failure



60

General disorders and 
administration site conditions
common fatigue

uncommon pyrexia, influenza like illness, malaise

* see section Description of selected adverse reactions “Bleeding” for source of information

Description of selected adverse reactions
The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were 
seen at higher frequency among tipranavir with ritonavir treated patients when compared with the 
comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with 
ritonavir administration. The clinical significance of these observations has not been fully explored.  

Hepatotoxicity 
After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/or ASAT abnormalities was 
higher in tipranavir with ritonavir patients compared with comparator arm patients (10% and 3.4%, 
respectively). Multivariate analyses showed that baseline ALAT or ASAT above DAIDS Grade 1 and 
co-infection with hepatitis B or C were risk factors for these elevations. Most patients were able to 
continue treatment with tipranavir with ritonavir. 

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4)

Hyperlipidaemia 
Grade 3 or 4 elevations of triglycerides occurred more frequently in the tipranavir with ritonavir arm 
compared with the comparator arm. At 48 weeks these rates were 25.2% of patients in the tipranavir
with ritonavir arm and 15.6% in the comparator arm.  

Bleeding 
This adverse reaction was identified through post-marketing surveillance but not observed in 
randomised controlled clinical trials (n=6300).
RESIST participants receiving tipranavir with ritonavir tended to have an increased risk of bleeding; at 
24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 
1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between 
treatment groups in coagulation parameters. The significance of this finding is being further 
monitored.
Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving tipranavir, 
many of whom had other medical conditions or were receiving concomitant medicinal products that 
may have caused or contributed to these events. However, in some cases the role of tipranavir cannot 
be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in 
patients in general, or preceding the development of ICH. Therefore, routine measurement of 
coagulation parameters is not currently indicated in the management of patients on Aptivus.
An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS 
such as those treated in the Aptivus clinical trials.

Rash
An interaction study in women between tipranavir, co-administered with low dose ritonavir, and 
ethinyl oestradiol/norethindrone demonstrated a high frequency of non-serious rash. In the RESIST 
trials, the risk of rash was similar between tipranavir with ritonavir and comparator arms (16.3% vs. 
12.5%, respectively; see section 4.4). No cases of Stevens-Johnson Syndrome or Toxic Epidermal 
Necrolysis have been reported in the clinical development programme of tipranavir.

Laboratory abnormalities
Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of 
patients in the tipranavir with ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST-
2) after 48-weeks were increased ASAT (6.1%), increased ALAT (9.7%), increased amylase (6.0%), 



61

increased cholesterol (4.2%), increased triglycerides (24.9%), and decreased white blood cell count 
(5.7%).

Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis, have been reported with protease 
inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4). Reactivation of herpes simplex and herpes 
zoster virus infections were observed in the RESIST trials.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). 
The frequency of this is unknown (see section 4.4).

Paediatric population
In an open-label, dose-finding study of tipranavir plus ritonavir (Trial 1182.14), 62 children aged 2 to 
12 years received Aptivus oral solution. In general, adverse reactions were similar to those seen in 
adults, with the exception of vomiting, rash and pyrexia which were reported more frequently in 
children than in adults. The most frequently reported moderate or severe adverse reactions in the 
48 week analyses are noted below. 

Most frequently reported moderate or severe adverse reactions in paediatric patients age 2 to < 
12 years (reported in 2 or more children, Trial 1182.14, 48 weeks analyses, Full Analysis Set).

Total patients treated (N) 62
Events [N(%)]
Diarrhoea 4 (6.5)
Vomiting 3 (4.8)
Nausea 3 (4.8)
Abdominal pain1 3 (4.8)
Pyrexia 4 (6.5)
Rash2 4 (6.5)
gamma GT increased 4 (6.5)
ALAT increased 2 (3.2)
Anaemia 2 (3.2)

1 Includes abdominal pain (N=1), dysphagia (N=1) and epigastric discomfort (N=1). 
2 Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash papular, erythema, rash 
maculo-papular, rash pruritic, and urticaria.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

Human experience with tipranavir overdose is very limited. No specific signs and symptoms of 
overdose are known. Generally, an increased frequency and higher severity of adverse reactions may 
result from overdose.

There is no known antidote for tipranavir overdose. Treatment of overdose should consist of general 
supportive measures, including monitoring of vital signs and observation of the patient’s clinical 
status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


62

lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed 
substance. Since tipranavir is highly protein bound, dialysis is unlikely to be beneficial in significant 
removal of this medicine.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE09

Mechanism of action
The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the 
cleavage and maturation of viral protein precursors. Tipranavir is a non-peptidic inhibitor of the HIV-1 
protease that inhibits viral replication by preventing the maturation of viral particles.

Antiviral activity in vitro
Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models 
of T-cell infection, with 50% and 90% effective concentrations (EC50 and EC90) ranging from 0.03 to 
0.07 µM (18-42 ng/ml) and 0.07 to 0.18 µM (42-108 ng/ml), respectively. Tipranavir demonstrates 
antiviral activity in vitro against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, 
H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in 
vitro to tipranavir with EC50 values ranging from 0.164-1 µM and 0.233-0.522 µM, respectively. 
Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-
fold in conditions where human serum is present. 

Resistance
The development of resistance to tipranavir in vitro is slow and complex. In one particular in vitro
resistance experiment, an HIV-1 isolate that was 87-fold resistant to tipranavir was selected after 9 
months, and contained 10 mutations in the protease: L10F, I13V, V32I, L33F, M36I, K45I, I54V/T, 
A71V, V82L, I84V as well as a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic 
experiments showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L, 
I84V) was required to confer > 10-fold resistance to tipranavir while the full 10-mutation genotype 
conferred 69-fold resistance to tipranavir. In vitro, there is an inverse correlation between the degree 
of resistance to tipranavir and the capacity of viruses to replicate. Recombinant viruses showing ≥ 3-
fold resistance to tipranavir grow at less than 1% of the rate detected for wild type HIV-1 in the same 
conditions. Tipranavir resistant viruses which emerge in vitro from wild-type HIV-1 show decreased 
susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and 
ritonavir but remain sensitive to saquinavir. 

Through a series of multiple stepwise regression analyses of baseline and on-treatment genotypes from 
all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/or 
reduced 48-week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 
58E, 69K, 74P, 82L/T, 83D and 84V. Clinical isolates that exhibited a  10-fold decrease in tipranavir 
susceptibility harboured 8 or more tipranavir-associated mutations. In Phase II and III clinical trials, 
276 patients with on-treatment genotypes have demonstrated that the predominant emerging mutations 
with tipranavir treatment are L33F/I/V, V82T/L and I84V. Combination of all three of these is usually 
required for reduced susceptibility. Mutations at position 82 occur via two pathways: one from pre-
existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.

Cross-resistance
Tipranavir maintains significant antiviral activity (< 4-fold resistance) against the majority of HIV-1 
clinical isolates showing post-treatment decreased susceptibility to the currently approved protease 
inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir. Greater 
than 10-fold resistance to tipranavir is uncommon (< 2.5% of tested isolates) in viruses obtained from 
highly treatment experienced patients who have received multiple peptidic protease inhibitors.



63

ECG evaluation
The effect of tipranavir with low dose of ritonavir on the QTcF interval was measured in a study in 
which 81 healthy subjects received the following treatments twice daily for 2.5 days: 
tipranavir/ritonavir (500/200 mg), tipranavir/ritonavir at a supra-therapeutic dose (750/200 mg), and 
placebo/ritonavir (-/200 mg). After baseline and placebo adjustment, the maximum mean QTcF 
change was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the 500/200 mg dose and 8.3 ms (1-sided 95% 
Upper CI: 10.8 ms) for the supra-therapeutic 750/200 mg dose. Hence tipranavir at therapeutic dose 
with low dose of ritonavir did not prolong the QTc interval but may do so at supratherapeutic dose.

Clinical pharmacodynamic data
This indication is based on the results of one phase II study investigating pharmacokinetics, safety and 
efficacy of Aptivus oral solution in mostly treatment-experienced children aged 2 to 12 years.

The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1 
and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts. RESIST-1 and 
RESIST-2 are ongoing, randomised, open-label, multicentre studies in HIV-positive, triple-class 
experienced patients, evaluating treatment with tipranavir 500 mg co-administered with low dose 
ritonavir 200 mg (twice daily) plus an optimised background regimen (OBR) individually defined for 
each patient based on genotypic resistance testing and patient history. The comparator regimen 
included a ritonavir-boosted PI (also individually defined) plus an OBR. The ritonavir-boosted PI was 
chosen from among saquinavir, amprenavir, indinavir or lopinavir/ritonavir.  

All patients had received at least two PI-based antiretroviral regimens and were failing a PI-based 
regimen at the time of study entry. At least one primary protease gene mutation from among 30N, 46I, 
46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than 
two mutations on codons 33, 82, 84 or 90.

After Week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of 
virologic response had the option of discontinuing treatment and switching over to tipranavir with 
ritonavir in a separate roll-over study. 

The 1483 patients included in the primary analysis had a median age of 43 years (range 17-80), were 
86% male, 75% white, 13% black and 1% Asian. In the tipranavir and comparator arms median 
baseline CD4 cell counts were 158 and 166 cells/mm3, respectively, (ranges 1-1893 and 1-
1184 cells/mm3); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log10 copies/ml, respectively 
(ranges 2.34-6.52 and 2.01-6.76 log10 copies/ml). 

Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. In both studies, a total of 
67% patient viruses were resistant and 22% were possibly resistant to the pre-selected comparator PIs. 
A total of 10% of patients had previously used enfuvirtide. Patients had baseline HIV-1 isolates with a 
median of 16 HIV-1 protease gene mutations, including a median of 3 primary protease gene 
mutations D30N, L33F/I, V46I/L, G48V, I50V, V82A/F/T/L, I84V, and L90M. With respect to 
mutations on codons 33, 82, 84 and 90 approximately 4% had no mutations, 24% had mutations at 
codons 82 (less than 1% of patients had the mutation V82L) and 90, 18% had mutations at codons 84 
and 90 and 53% had at least one key mutation at codon 90. One patient in the tipranavir arm had four 
mutations. In addition the majority of participants had mutations associated with both NRTI and 
NNRTI resistance. Baseline phenotypic susceptibility was evaluated in 454 baseline patient samples.  
There was an average decrease in susceptibility of 2-fold wild type (WT) for tipranavir, 12-fold WT 
for amprenavir, 55-fold WT for atazanavir, 41-fold WT for indinavir, 87-fold WT for lopinavir, 41-
fold WT for nelfinavir, 195-fold WT for ritonavir, and 20-fold WT for saquinavir.

Combined 48-week treatment response (composite endpoint defined as patients with a confirmed 
1 log RNA drop from baseline and without evidence of treatment failure) for both studies was 34% 
in the tipranavir with ritonavir arm and 15% in the comparator arm. Treatment response is presented 
for the overall population (displayed by enfuvirtide use), and detailed by PI strata for the subgroup of 
patients with genotypically resistant strains in the Table below. 



64

Treatment response* at week 48 (pooled studies RESIST-1 and RESIST-2 in treatment-
experienced patients)

RESIST study Tipranavir /RTV CPI/RTV** p-value

n (%) N n (%) N
Overall population
FAS
PP

255 (34.2)
171 (37.7)

746
454

114 (15.5)
74 (17.1)

737
432

0.0001
0.0001

- with ENF (FAS) 85 (50.0) 170 28 (20.7) 135 0.0001
- without ENF (FAS) 170 (29.5) 576 86 (14.3) 602 0.0001

Genotypically Resistant
LPV/rtv  
FAS
PP

66 (28.9)
47 (32.2)

228
146

23 (9.5)
13 (9.1)

242
143

0.0001
0.0001

APV/rtv
FAS
PP

50 (33.3)
38 (39.2)

150
97

22 (14.9)
17 (18.3)

148
93

0.0001
0.0010

SQV/rtv
FAS
PP

22 (30.6)
11 (28.2)

72
39

5 (7.0)
2 (5.7)

71
35

0.0001
0.0650

IDV/rtv
FAS
PP

6 (46.2)
3 (50.0)

13
6

1 (5.3)
1 (7.1)

19
14

0.0026
0.0650

* Composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without 
evidence of treatment failure 
** Comparator PI/RTV: LPV/r 400 mg/100 mg twice daily (n=358), IDV/r 800 mg/100 mg twice 
daily (n=23), SQV/r 1000 mg/100 mg twice daily or 800 mg/200 mg twice daily (n=162), APV/r 
600 mg/100 mg twice daily (n=194)
ENF Enfuvirtide; FAS Full Analysis Set; PP Per Protocol; APV/rtv Amprenavir/ritonavir; IDV/rtv
Indinavir/ritonavir; LPV/rtv Lopinavir/ritonavir; SQV/rtv Saquinavir/ritonavir

Combined 48-week median time to treatment failure for both studies was 115 days in the tipranavir
with ritonavir arm and 0 days in the comparator arm (no treatment response was imputed to day 0).

Through 48 weeks of treatment, the proportion of patients in the tipranavir with ritonavir arm 
compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/ml was 30% and 14% 
respectively, and with HIV-1 RNA < 50 copies/ml was 23% and 10% respectively. Among all 
randomised and treated patients, the median change from baseline in HIV-1 RNA at the last 
measurement up to Week 48 was -0.64 log10 copies/ml in patients receiving tipranavir with ritonavir 
versus -0.22 log10 copies/ml in the comparator PI/ritonavir arm.

Among all randomised and treated patients, the median change from baseline in CD4+ cell count at 
the last measurement up to Week 48 was +23 cells/mm3 in patients receiving tipranavir with ritonavir 
(N=740) versus +4 cells/mm3 in the comparator PI/ritonavir (N=727) arm.

The superiority of tipranavir co-administered with low dose ritonavir over the comparator protease 
inhibitor/ritonavir arm was observed for all efficacy parameters at week 48. It has not been shown that 
tipranavir is superior to these boosted comparator protease inhibitors in patients harbouring strains 
susceptible to these protease inhibitors. RESIST data also demonstrate that tipranavir co-administered 
with low dose ritonavir exhibits a better treatment response at 48 weeks when the OBR contains 
genotypically available antiretroviral agents (e.g. enfuvirtide).

At present there are no results from controlled trials evaluating the effect of tipranavir on clinical 
progression of HIV.



65

Paediatric population
HIV-positive, paediatric patients, aged 2 through 18 years, were studied in a randomized, open-label, 
multicenter study (trial 1182.14). Patients were required to have a baseline HIV-1 RNA concentration 
of at least 1500 copies/ml, were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years) 
and randomized to receive one of two tipranavir with ritonavir dose regimens: 375 mg/m2/150 mg/m2

dose, compared to the 290 mg/m2/115 mg/m2 dose, plus background therapy of at least two non-
protease inhibitor antiretroviral medicinal products, optimized using baseline genotypic resistance 
testing. All patients initially received Aptivus oral solution. Paediatric patients who were 12 years or 
older and received the maximum dose of 500 mg/200 mg twice daily could change to Aptivus capsules 
from study day 28. The trial evaluated pharmacokinetics, safety and tolerability, as well as virologic 
and immunologic responses through 48 weeks.   

The available clinical data do not support the use of Aptivus oral solution in adolescents or adults. 
Compared to the capsules, tipranavir exposure is higher when administering the same dose as oral 
solution (see section 5.2). Due to this and to the high vitamin E content of the oral solution, the risk of 
adverse reactions (type, frequency and/or severity) may be higher than with the capsule formulation. 
In patients less than 12 years of age, however, the oral solution is the only available option for 
treatment with tipranavir, as no data are available on the efficacy and safety of Aptivus capsules in 
children less than 12 years of age. Since Aptivus capsules and oral solution are not bioequivalent, 
results obtained with the oral solution cannot be extrapolated to the capsules (see also section 5.2). 
Moreover, in patients with a body surface area of less than 1.33 m² appropriate dose adjustments 
cannot be achieved with the capsule formulation. These factors lead to the conclusion that the benefits 
outweigh the risks of Aptivus oral solution only in children between 2 and 12 years of age without any 
other therapeutic option (see section 4.1).

The baseline characteristics and the key efficacy results at 48 weeks for the paediatric patients 
receiving Aptivus oral solution are displayed in the tables below.

Baseline characteristics for patients 2 - <12 years treated with Aptivus oral solution

Variable Value
Number of Patients 62
Age-Median (years) 8.1
Gender % Male 59.7%
Race % White 71.0%

% Black 25.8%
% Asian 3.2%

Baseline HIV-1 RNA 
(log10 copies/ml)

Median 
(Min – Max)

4.8 (3.3 – 6.0)

% with VL  > 
100,000 copies/ml

37.1%

Baseline CD4+ 
(cells/mm3)

Median
(Min – Max)

600 (24 – 2578)

% ≤ 200 15.5%

Baseline % CD4+ cells Median 
(Min – Max)

21.9% (1.5% –
44.0%)

Previous ADI* % with Category C 48.4%
Treatment history % with any ARV 96.8%

Median # previous 
NRTIs

4

Median # previous 
NNRTIs

1

Median # previous 
PIs

1

* AIDS defining illness



66

Key efficacy results at 48 weeks for patients 2 - <12 years treated with Aptivus oral solution

Endpoint Result
Number of patients 62
Primary efficacy endpoint: 
% with VL < 400

50.0%

Median change from baseline 
in log10 HIV-1 RNA (copies/ml) 

-2.06

Median change from baseline 
in CD4+ cell count (cells/mm3) 

167

Median change from baseline 
in % CD4+ cells 

5%

Analyses of tipranavir resistance in treatment experienced patients
Tipranavir with ritonavir response rates in the RESIST studies were assessed by baseline tipranavir 
genotype and phenotype.  Relationships between baseline phenotypic susceptibility to tipranavir, 
primary PI mutations, protease mutations at codons 33, 82, 84 and 90, tipranavir resistance-associated 
mutations, and response to tipranavir with ritonavir therapy were assessed.

Of note, patients in the RESIST studies had a specific mutational pattern at baseline of at least one 
primary protease gene mutation among codons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 
90M, and no more than two mutations on codons 33, 82, 84 or 90.

The following observations were made:

 Primary PI mutations
Analyses were conducted to assess virological outcome by the number of primary PI mutations (any 
change at protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90) present at baseline. 
Response rates were higher in tipranavir with ritonavir patients than comparator PI boosted with 
ritonavir in new enfuvirtide patients, or patients without new enfuvirtide. However, without new 
enfuvirtide some patients began to lose antiviral activity between weeks 4 and 8.

 Mutations at protease codons 33, 82, 84 and 90
A reduced virological response was observed in patients with viral strains harbouring two or more 
mutations at HIV protease codons 33, 82, 84 or 90, and not receiving new enfuvirtide.

 Tipranavir resistance-associated mutations
Virological response to tipranavir with ritonavir therapy has been evaluated using a tipranavir-
associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients. This score 
(counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or 
reduced viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 
69K, 74P, 82L/T, 83D and 84V) was applied to baseline viral protease sequences. A correlation 
between the tipranavir mutation score and response to tipranavir with ritonavir therapy at week 48 has 
been established. 

This score has been determined from the selected RESIST patient population having specific mutation 
inclusion criteria and therefore extrapolation to a wider population mandates caution.

At 48-weeks, a higher proportion of patients receiving tipranavir with ritonavir achieved a treatment 
response in comparison to the comparator protease inhibitor/ritonavir for nearly all of the possible 
combinations of genotypic resistance mutations (see table below).



67

Proportion of patients achieving treatment response at Week 48 (confirmed ≥1 log10 copies/ml 
decrease in viral load compared to baseline), according to tipranavir baseline mutation score 
and enfuvirtide use in RESIST patients

New ENF No New 
ENF*

Number of 
TPV Score 
Mutations**

TPV/r TPV/r 

0,1 73% 53%
2 61% 33%
3 75% 27%
4 59% 23%

≥ 5 47% 13%
All patients 61% 29%

* Includes patients who did not receive ENF and those who were previously treated with and 
continued ENF
**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, 
I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V
ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

Sustained HIV-1 RNA decreases up to week 48 were mainly observed in patients who received 
tipranavir with ritonavir and new enfuvirtide. If patients did not receive tipranavir with ritonavir with 
new enfuvirtide, diminished treatment responses at week 48 were observed, relative to new enfuvirtide 
use (see Table below).

Mean decrease in viral load from baseline to week 48, according to tipranavir baseline mutation 
score and enfuvirtide use in RESIST patients

New ENF No New 
ENF*

Number of  
TPV Score 
Mutations**

TPV/r TPV/r 

0, 1 -2.3 -1.6
2 -2.1 -1.1
3 -2.4 -0.9
4 -1.7 -0.8

≥ 5 -1.9 -0.6
All patients -2.0 -1.0

* Includes patients who did not receive ENF and those who were previously treated with and 
continued ENF
** Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, 
M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V
ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

 Tipranavir phenotypic resistance
Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing 
virological response.  Isolates with baseline fold change of >0 to 3 are considered susceptible; isolates 
with >3 to 10 fold changes have decreased susceptibility; isolates with >10 fold changes are resistant.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to 
change with additional data, and it is recommended to always consult current interpretation systems 
for analysing resistance test results.



68

5.2 Pharmacokinetic properties

In order to achieve effective tipranavir plasma concentrations and a twice daily dosing regimen, 
coadministration of tipranavir with low dose ritonavir twice daily is essential (see section 4.2). 
Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (P-gp) 
efflux pump and possibly intestinal cytochrome P450 CYP3A as well. As demonstrated in a dose-
ranging evaluation in 113 HIV-negative healthy male and female volunteers, ritonavir increases AUC0-
12h, Cmax and Cmin and decreases the clearance of tipranavir. 500 mg tipranavir co-administered with 
low dose ritonavir (200 mg; twice daily) was associated with a 29-fold increase in the geometric mean 
morning steady-state trough plasma concentrations compared to tipranavir 500 mg twice daily without 
ritonavir. 

Absorption
Absorption of tipranavir in humans is limited, though no absolute quantification of absorption is 
available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor and appears to be a potent P-gp inducer 
as well. Data suggest that, although ritonavir is a P-gp inhibitor, the net effect of Aptivus, co-
administered with low dose ritonavir, at the proposed dose regimen at steady-state, is P-gp induction. 
Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon 
the dosage used. With repeated dosing, tipranavir plasma concentrations are lower than predicted from 
single dose data, presumably due to hepatic enzyme induction. Steady-state is attained in most subjects 
after 7 days of dosing. Tipranavir, co-administered with low dose ritonavir, exhibits linear 
pharmacokinetics at steady state.

Dosing with Aptivus capsules 500 mg twice daily concomitant with 200 mg ritonavir twice daily for 2 
to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration (Cmax) 
of 94.8 ± 22.8 µM for female patients (n=14) and 77.6 ± 16.6 µM for male patients (n=106), 
occurring approximately 3 hours after administration. The mean steady-state trough concentration 
prior to the morning dose was 41.6 ± 24.3 µM for female patients and 35.6 ± 16.7 µM for male 
patients. Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 µM•h (CL=1.15 l/h) for 
female patients and 710 ± 207 µM•h (CL=1.27 l/h) for male patients. The mean half-life was 
5.5 (females) or 6.0 hours (males). 

Effects of food on oral absorption
Food improves the tolerability of tipranavir with ritonavir. Therefore Aptivus, co-administered with 
low dose ritonavir, should be given with food. 

Absorption of tipranavir, co-administered with low dose ritonavir, is reduced in the presence of 
antacids (see section 4.5). 

Distribution
Tipranavir is extensively bound to plasma proteins (>99.9%). From clinical samples of healthy 
volunteers and HIV-1 positive subjects who received tipranavir without ritonavir the mean fraction of 
tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015%  0.006%; 
HIV-positive subjects 0.019%  0.076%). Total plasma tipranavir concentrations for these samples 
ranged from 9 to 82 M. The unbound fraction of tipranavir appeared to be independent of total 
concentration over this concentration range.  

No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal 
fluid or semen.

Biotransformation
In vitro metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant 
CYP isoform involved in tipranavir metabolism. 

The oral clearance of tipranavir decreased after the addition of ritonavir which may represent 
diminished first-pass clearance of the substance at the gastrointestinal tract as well as the liver. 



69

The metabolism of tipranavir in the presence of low dose ritonavir is minimal. In a 14C-tipranavir 
human study (500 mg 14C-tipranavir with 200 mg ritonavir, twice daily), unchanged tipranavir was 
predominant and accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or 
12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2% 
or less of the plasma radioactivity). In faeces, unchanged tipranavir represented the majority of faecal 
radioactivity (79.9% of faecal radioactivity). The most abundant faecal metabolite, at 4.9% of faecal 
radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir 
was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 
11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.

Elimination
Administration of 14C-tipranavir to subjects (n = 8) that received 500 mg tipranavir with 200 mg 
ritonavir twice daily dosed to steady-state demonstrated that most radioactivity (median 82.3%) was 
excreted in faeces, while only a median of 4.4% of the radioactive dose administered was recovered in 
urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The 
effective mean elimination half-life of tipranavir with ritonavir in healthy volunteers (n = 67) and 
HIV-infected adult patients (n = 120) was approximately 4.8 and 6.0 hours, respectively, at steady 
state following a dose of 500 mg/200 mg twice daily with a light meal. 

Special populations
Although data available at this stage are currently limited to allow a definitive analysis, they suggest 
that the pharmacokinetic profile is unchanged in older people and comparable between races. By 
contrast, evaluation of the steady-state plasma tipranavir trough concentrations at 10-14 h after dosing 
from the RESIST-1 and RESIST-2 studies demonstrate that females generally had higher tipranavir 
concentrations than males. After four weeks of Aptivus 500 mg with 200 mg ritonavir (twice daily) 
the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males. 
This difference in concentrations does not warrant a dose adjustment.

Renal impairment
Tipranavir pharmacokinetics have not been studied in patients with renal impairment. However, since 
the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in 
patients with renal impairment.

Hepatic impairment
In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 controls, the single 
and multiple dose exposure of tipranavir and ritonavir were increased in patients with hepatic 
impairment but still within the range observed in clinical studies.  No dosing adjustment is required in 
patients with mild hepatic impairment but patients should be closely monitored (see sections 4.2 and 
4.4).

The influence of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment on the 
multiple dose pharmacokinetics of either tipranavir or ritonavir has so far not been investigated. 
Tipranavir is contraindicated in moderate or severe hepatic impairment (see sections 4.2 and 4.3).

Paediatric population
The oral solution has been shown to have greater bioavailability than the soft capsule formulation.

5.3 Preclinical safety data

Animal toxicology studies have been conducted with tipranavir alone, in mice, rats and dogs, and co-
administered with ritonavir (3.75:1 w/w ratio) in rats and dogs. Studies with co-administration of 
tipranavir and ritonavir did not reveal any additional toxicological effects when compared to those 
seen in the tipranavir single agent toxicological studies.

The predominant effects of repeated administration of tipranavir across all species toxicologically 
tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy). The 
effects were reversible with termination of treatment. Additional changes included bleeding in rats at 



70

high doses (rodents specific). Bleeding observed in rats was associated with prolonged prothrombin 
time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent 
factors. The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol 
polyethylene glycol 1000 succinate) from 2,322 IU/m² upwards in rats resulted in a significant 
increase in effects on coagulation parameters, bleeding events and death. In preclinical studies of 
tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir 
and vitamin E has not been studied in dogs. 

The majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which 
are equivalent to or even below the human exposure levels at the recommended clinical dose. 

In in vitro studies, tipranavir was found to inhibit platelet aggregation when using human platelets (see 
section 4.4) and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure 
observed in patients receiving Aptivus with ritonavir. The clinical implications of these findings are 
not known.

In a study conducted in rats with tipranavir at systemic exposure levels (AUC) equivalent to human 
exposure at the recommended clinical dose, no adverse effects on mating or fertility were observed. At 
maternal doses producing systemic exposure levels similar to or below those at the recommended 
clinical dose, tipranavir did not produce teratogenic effects. At tipranavir exposures in rats at 0.8-fold 
human exposure at the clinical dose, foetal toxicity (decreased sternebrae ossification and body 
weights) was observed. In pre- and post-natal development studies with tipranavir in rats, growth 
inhibition of pups was observed at maternally toxic doses approximating 0.8-fold human exposure. 

Carcinogenicity studies of tipranavir in mice and rats revealed tumourigenic potential specific for 
these species, which are regarded as of no clinical relevance. Tipranavir showed no evidence of 
genetic toxicity in a battery of in vitro and in vivo tests. 

In Aptivus oral solution, a degradation impurity (5-trifluoro-2-methylpyridinol, 5-TFMP) may be 
present. Highly purified 5-TFMP has been tested using the in vitro Ames bacterial reverse mutation 
test and has shown positive results. Therefore, 5-TFMP is considered a mutagen with unknown 
carcinogenic potential. Given the expected limited treatment duration of the oral solution the clinical 
relevance is uncertain.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Macrogol 
Vitamin E polyethylene glycol succinate
Purified water
Propylene glycol 
Mono/diglycerides of caprylic/capric acid 
Sucralose
Butter mint (flavouring)
Butter toffee (flavouring) 
Ascorbic acid

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

18 months.



71

In use storage: 60 days, after first opening of the bottle. It is advisable that the patient writes the date 
of opening the bottle on the label and/or carton.

6.4 Special precautions for storage

Store between 15°C and 25ºC. Do not refrigerate or freeze.

6.5 Nature and contents of container

Amber glass bottle, with two-piece plastic child-resistant closure (outer shell high density 
polyethylene (HDPE), inner shell polypropylene resin with a foamed laminated polyethylene liner.. 
Each pack contains 1 bottle of 95 ml oral solution and is supplied with a clear polypropylene 5 ml oral 
syringe, HDPE syringe tip cap and clear LDPE bottle-syringe adapter.

6.6 Special precautions for disposal and other handling

Before taking Aptivus it should be checked that the oral solution is clear and whether there are crystals 
or other particles at the bottom of the bottle. A small amount of crystals may be observed in the bottle, 
which does not affect the potency or safety of the product. If observed, crystals are typically seen as a 
paper-thin layer on the bottom when the bottle is stored upright. Dosing by means of the measuring 
device remains accurate even when crystals are observed. If there is more than a thin layer of crystals 
at the bottom of the bottle or uncertainty about the amount of crystals observed, the bottle should be 
returned for a replacement as soon as possible. Until the bottle is exchanged the patient should 
continue to take the usual doses of the oral solution. Patients should be instructed to observe closely 
for crystals. 

The exact dose should be measured using the supplied measuring syringe and adapter, as follows:

1. Open the bottle by pressing down on the cap and turning in an anti-clockwise direction. 
2. Remove the syringe cap covering the tip of the oral syringe (the cap will not be attached if this 

is the first time the oral syringe has been used) and insert the oral syringe into the adapter 
located in the neck of the bottle. Make sure the oral syringe is tightly inserted.

3. Turn the bottle upside down and gently withdraw the required amount of Aptivus oral solution.
4. Administer Aptivus oral solution immediately. The maximum volume which can be withdrawn 

at one time is 5 ml (equivalent to 500 mg tipranavir), which is the maximum single dose for a 
child with BSA > 1.33 m2.

5. After use of the oral syringe, reapply the syringe cap. 

No special requirements for disposal. 

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/05/315/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 October 2005



72

Date of latest renewal: 19 June 2015

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency  
http://www.ema.europa.eu/ 



73

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT



74

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, D-55216 Ingelheim am Rhein, 
Germany.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

• Periodic safety update reports (PSURs)
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk management plan (RMP)
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP.

An updated RMP should be submitted
 At the request of the European Medicines Agency
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.



75

ANNEX III

LABELLING AND PACKAGE LEAFLET



76

A. LABELLING



77

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

FOLDING BOX/OUTER PACKAGING

1. NAME OF THE MEDICINAL PRODUCT

Aptivus 250 mg soft capsules
tipranavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each soft capsule contains 250 mg tipranavir

3. LIST OF EXCIPIENTS

Contains macrogolglycerol ricinoleate, sorbitol and ethanol (see package leaflet for further 
information)

4. PHARMACEUTICAL FORM AND CONTENTS

120 soft capsules 

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP 

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator. 
In use storage: 60 days (below 25°C) after first opening of the bottle.
Date of first opening of the bottle:



78

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/05/315/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Aptivus 250 mg

17. UNIQUE IDENTIFIER --- 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER --- HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal
product]



79

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE/IMMEDIATE PACKAGING

1. NAME OF THE MEDICINAL PRODUCT

Aptivus 250 mg soft capsules
tipranavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each soft capsule contains 250 mg tipranavir

3. LIST OF EXCIPIENTS

Contains macrogolglycerol ricinoleate, sorbitol and ethanol (see package leaflet for further 
information)

4. PHARMACEUTICAL FORM AND CONTENTS

120 soft capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP 

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator. 
In use storage: 60 days (below 25°C) after first opening of the bottle.
Date of first opening of the bottle:



80

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/05/315/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER --- 2D BARCODE

18. UNIQUE IDENTIFIER --- HUMAN READABLE DATA



81

PARTICULARS TO APPEAR ON THE OUTER 

FOLDING BOX/OUTER PACKAGING

1. NAME OF THE MEDICINAL PRODUCT

Aptivus 100 mg/ml oral solution
tipranavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each ml contains 100 mg tipranavir

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

95 ml oral solution (1 bottle)
Oral syringe

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP 

9. SPECIAL STORAGE CONDITIONS

Store between 15°C and 25ºC. Do not refrigerate or freeze
After first opening of the bottle, the product can be used for 60 days.
Date of first opening of the bottle:



82

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/05/315/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Aptivus 100 mg/ml

17. UNIQUE IDENTIFIER --- 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER --- HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal
product]



83

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE/IMMEDIATE PACKAGING

1. NAME OF THE MEDICINAL PRODUCT

Aptivus 100 mg/ml oral solution
tipranavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each ml contains 100 mg tipranavir

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

95 ml 

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP 

9. SPECIAL STORAGE CONDITIONS

Store between 15°C and 25ºC. Do not refrigerate or freeze
After first opening of the bottle, the product can be used for 60 days.
Date of first opening:



84

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/05/315/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER --- 2D BARCODE

18. UNIQUE IDENTIFIER --- HUMAN READABLE DATA



85

B. PACKAGE LEAFLET



86

Package leaflet: Information for the user

Aptivus 250 mg soft capsules
tipranavir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, please ask your doctor or your pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Aptivus is and what it is used for
2. What you need to know before you take Aptivus
3. How to take Aptivus
4. Possible side effects
5. How to store Aptivus
6. Contents of the pack and other information

If Aptivus has been prescribed for your child, please note that all information in this leaflet is 
addressed to your child (in this case please read “your child” instead of “you”).

1. What Aptivus is and what it is used for

Aptivus contains the active substance tipranavir. It belongs to a group of medicines called protease 
inhibitors and is used in the treatment of Human Immunodeficiency Virus (HIV) infection. It blocks 
an enzyme called protease that is involved in the reproduction of HIV. When the enzyme is blocked, 
the virus does not reproduce normally, slowing down the infection. You must take Aptivus together 
with:

 low dose ritonavir (this helps Aptivus to reach a high enough level in your blood)
 other HIV medicines. Your doctor, together with you, will decide which other medicines you 

should take. This will depend on, for example:
 which other medicines you have already taken for HIV
 which medicines your HIV is resistant to. If your HIV is resistant to some HIV 

medicines, this means that the medicine will not work so well, or will not work at all.

Aptivus is specifically used for the treatment of HIV which is resistant to most other protease 
inhibitors. Before starting treatment, your doctor will have taken blood samples to test the resistance 
of your HIV. These tests will have confirmed that the HIV in your blood is resistant to most other 
protease inhibitors. Aptivus treatment is therefore appropriate for you. You should not use Aptivus if 
you have never received antiretroviral therapy or have other antiretroviral options available.

Aptivus soft capsules are indicated for:
 adolescents 12 years of age or older
 adults



87

2. What you need to know before you take Aptivus

You must take Aptivus in combination with low dose ritonavir and other antiretroviral 
medicines. It is therefore important that you know about these medicines too. You should 
therefore carefully read the Package Leaflets of ritonavir and your other antiretroviral
medicines. If you have any further questions about ritonavir or the other medicines you are 
prescribed, please ask your doctor or pharmacist.

Do not take Aptivus
- if you are allergic to tipranavir or any of the other ingredients of this medicine (listed in section 

6)
- if you have moderate to severe liver problems. Your doctor will take a blood sample to test how 

well your liver is working (your liver function). Depending on your liver function you may have 
to delay or stop Aptivus treatment

- if you are currently taking products containing:
- rifampicin (used to treat tuberculosis)
- cisapride (used to treat stomach problems)
- pimozide or sertindole (used to treat schizophrenia)
- quetiapine (used to treat schizophrenia, bipolar disorder and major depressive 

disorder)
- lurasidone (used to treat schizophrenia)
- triazolam or oral midazolam (taken by mouth). These medicines are used to treat 

anxiety or sleep disorders
- ergot derivatives (used to treat headaches)
- astemizole or terfenadine (used to treat allergies or hay fever)
- simvastatin or lovastatin (used to lower blood cholesterol)
- amiodarone, bepridil, flecainide, propafenone or quinidine (used to treat heart 

disorders)
- metoprolol (used to treat heart failure)
- alfuzosin and sildenafil (when used to treat a rare blood vessel disorder characterized 

by increased pressure in the pulmonary artery)
- colchicine (when used to treat gout flares in patients with kidney or liver disease).

Do not take products containing St John’s wort (a herbal remedy for depression). This may stop 
Aptivus from working properly.

Warnings and precautions
Talk to your doctor or pharmacist before taking Aptivus.

Tell your doctor if you have:
- type A or B haemophilia
- diabetes
- liver disease.

If you have:
- high liver function test results
- hepatitis B or C infection
you are at increased risk of severe and potentially fatal liver damage while taking Aptivus. Your 
doctor will monitor your liver function by blood tests before and during Aptivus treatment. If you have 
liver disease or hepatitis, your doctor will decide if you need additional testing. You should inform 
your doctor as soon as possible if you notice the signs or symptoms of hepatitis:
- fever
- malaise (feeling generally unwell)
- nausea (upset stomach)
- vomiting
- abdominal pain
- tiredness



88

- jaundice (yellowing of the skin or the eyeballs)

Aptivus is not a cure for HIV infection:
You should know that you may continue to develop infections and other illnesses associated with HIV 
disease. You should therefore remain in regular contact with your doctor. You can still pass on HIV 
when taking this medicine, although the risk is lowered by effective antiretroviral therapy. Discuss 
with your doctor the precautions needed to avoid infecting other people.

Rash:
Mild to moderate rash, including:
- hives
- rash with flat or raised small red spots
- sensitivity to the sun
have been reported in approximately 1 in 10 patients receiving Aptivus. Some patients who developed 
rash also had:
- joint pain or stiffness
- throat tightness
- generalized itching

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs 
and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is 
started. It is believed that these symptoms are due to an improvement in the body’s immune response, 
enabling the body to fight infections that may have been present with no obvious symptoms. If you 
notice any symptoms of infection (for example fever, enlarged lymph nodes), please inform your
doctor immediately.

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for the 
treatment of your HIV infection. Autoimmune disorders may occur many months after the start of 
treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, 
weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, 
tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

Tell your doctor if you experience fainting or a sensation of abnormal heart beats. Aptivus in 
combination with low dose ritonavir may cause changes in your heart rhythm and the electrical 
activity of your heart. These changes may be seen on an ECG (electrocardiogram).

Bone problems: Some patients taking combination antiretroviral therapy may develop a bone disease 
called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe 
immunosuppression, higher body mass index, among others, may be some of the many risk factors for 
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the 
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor.

Children
Aptivus soft capsules should not be used by children under 12 years of age.

Older people
If you are older than 65 years your doctor will exercise caution when prescribing Aptivus soft capsules 
to you and will closely monitor your therapy. Tipranavir has been used in limited number of patients 
65 years or older.

Other medicines and Aptivus
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription.



89

This is very important. If you take other medicines at the same time as Aptivus and ritonavir, this can 
strengthen or weaken the effect of the medicines. These effects are called interactions, and can lead to 
serious side effects, or prevent proper control of other conditions you may have.

Interactions with other HIV medicines:
- etravirine belongs to a class of HIV medicines called non-nucleoside reverse transcriptase 

inhibitors (NNRTIs). Taking Aptivus with etravirine is not recommended.

- abacavir and zidovudine. These belong to a class of HIV medicines called nucleoside reverse 
transcriptase inhibitors (NRTIs). Your doctor will only prescribe you abacavir and zidovudine if 
you are unable to take other NRTIs. 

- didanosine: If you are taking didanosine enteric coated tablets, you should take them at least 
two hours before or after Aptivus.

- emtricitabine: If you are taking emtricitabine your kidney function should be checked before 
initiation of Aptivus.

- rilpivirine: If you are taking rilpivirine, your doctor will monitor you closely.

- Protease Inhibitors (PIs): Taking Aptivus may cause large decreases in the blood levels of other 
HIV protease inhibitors. For example the protease inhibitors amprenavir, atazanavir, lopinavir 
and saquinavir will be decreased.
Taking Aptivus, with atazanavir, may cause the blood levels of Aptivus and ritonavir to increase 
a lot. 
Your doctor will carefully consider whether to treat you with combinations of Aptivus and 
protease inhibitors.

Other medicines with which Aptivus may interact include:
- oral contraceptives/hormone replacement therapy (HRT): If you are taking the contraceptive pill 

to prevent pregnancy you should use an additional or different type of contraception (e.g. barrier 
contraception like condoms). Generally, it is not recommended to take Aptivus, with ritonavir, 
together with oral contraceptives or hormone replacement therapy (HRT). You should check 
with your doctor if you do wish to continue taking oral contraceptives or HRT. If you use oral 
contraceptives or HRT you have an increased chance of developing a skin rash while taking 
Aptivus. If a rash occurs, it is usually mild to moderate. You should talk to your doctor as you 
may need to temporarily stop taking either Aptivus or your oral contraceptives or HRT

- carbamazepine, phenobarbital and phenytoin (used to treat epilepsy). These may decrease the 
effectiveness of Aptivus.

- sildenafil, vardenafil, tadalafil (medicines used to produce and maintain an erection). The effects 
of sildenafil and vardenafil are likely to be increased if you take them with Aptivus. You should 
not be prescribed tadalafil until you have been taking Aptivus for 7 days or more.

- omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole (proton pump inhibitors 
used to reduce the gastric acid production)

- metronidazole (used to treat infections) 
- disulfiram (used to treat alcohol dependence)
- buprenorphine/naloxone (medicines used to treat severe pain)
- cyclosporin, tacrolimus, sirolimus (used to prevent organ rejection (to suppress the immune 

system))
- warfarin (used to treat and prevent thrombosis)
- digoxin (used to treat heart arrhythmias and heart failure)
- antifungal medications including fluconazole, itraconazole, ketoconazole or voriconazole

The following medicines are not recommended:
- fluticasone (used to treat asthma)
- atorvastatin (used to lower blood cholesterol)
- salmeterol (used to achieve long-term asthma control, bronchospasm prevention with COPD)



90

- bosentan (used to treat pulmonary artery hypertension)
- halofantrine or lumefantrine (used to treat malaria)
- tolterodine (used to treat overactive bladder (with symptoms of urinary frequency, urgency, or 

urge incontinence))
- boceprevir and telaprevir (used to treat hepatitis C)
- cobicistat and products containing cobicistat (used to increase effectiveness of HIV medicines).

Aptivus may lead to a loss of effectiveness of some medicines including:
- methadone, meperidine (pethidine), used as morphine substitutes

Your doctor may have to increase or decrease the dose of other medicines which you take together 
with Aptivus. Examples include:
- rifabutin and clarithromycin (antibiotics)
- theophylline (used to treat asthma) 
- desipramine, trazodone and bupropion (used to treat depression; bupropion is also used for 

smoking cessation)
- midazolam (when given by injection); midazolam is a sedative used to treat anxiety and to help 

you sleep
- rosuvastatin or pravastatin (used to lower blood cholesterol)
- colchicine (used to treat gout flares with normal kidney and liver function)
- raltegravir (used to treat HIV infection)
- dolutegravir (used to treat HIV infection).

If you take aluminium- and magnesium-based antacid (used to treat dyspepsia/gastrooesophageal 
reflux), the time interval between Aptivus and antacid should be at least two hours.

Tell your doctor if you receive medicines such as blood-thinning agents, or if you are taking vitamin 
E. Your doctor may wish to consider certain precautionary measures in such circumstances.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. It is not known whether Aptivus may 
be used safely during pregnancy. You must not breast-feed your baby because it is possible that the 
baby can become HIV-infected through the breast milk. See also Section 2, under “Oral 
contraceptives/hormone replacement therapy (HRT)”.
Aptivus contains very small amounts of alcohol (see Aptivus capsules contain ethanol). 

Driving and using machines
Some of the side effects of Aptivus may affect your ability to drive or operate machinery (e.g. 
dizziness and sleepiness). If affected, you should not drive or operate machinery.

Aptivus capsules contain ethanol, macrogolglycerol ricinoleate and sorbitol (E420)
Aptivus contains 100 mg of alcohol (ethanol) in each capsule. The amount in 250 mg of this medicine 
(i.e. one capsule) is equivalent to less than 3 ml of beer, or than 1 ml of wine. The small amount of 
alcohol in this medicine will not have any noticeable effects. 

Aptivus also contains macrogolglycerol ricinoleate which may cause stomach upset and diarrhoea.

This medicine contains 12.6 mg of sorbitol in each capsule.

3. How to take Aptivus

Always take this medicine exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are not sure. You must take Aptivus together with ritonavir. 

The recommended dose for an adult or an adolescent 12 years and above is:



91

- 500 mg (two 250 mg capsules) Aptivus together with 
- 200 mg (two 100 mg capsules) ritonavir
twice per day with food. 

Oral use.
Aptivus capsules should be taken with food, swallowed whole and must not be opened or chewed.

Always take this medicine in combination with other antiretroviral medicines. You should follow the 
instructions for these medicines within the supplied Package Leaflets.

You should continue to take Aptivus for as long as your doctor tells you.

If you take more Aptivus than you should
Inform your doctor as soon as possible if you take more than the prescribed dose of Aptivus.

If you forget to take Aptivus
If you miss a dose of Aptivus or ritonavir by more than 5 hours, wait and then take the next dose of 
Aptivus and ritonavir at the regularly scheduled time. If you miss a dose of Aptivus and/or ritonavir by 
less than 5 hours, take your missed dose immediately. Then take your next dose of Aptivus and 
ritonavir at the regularly scheduled time. 

Do not take a double dose to make up for a forgotten dose.

If you stop taking Aptivus
It has been shown that taking all doses at the appropriate times:
- greatly increases the effectiveness of your combination antiretroviral medicines
- reduces the chances of your HIV becoming resistant to your antiretroviral medicines

Therefore, it is important that you continue taking Aptivus correctly, as described above. Do NOT stop 
taking Aptivus unless your doctor instructs you to do so.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes. 

Like all medicines, this medicine can cause side effects, although not everybody gets them. It may be 
difficult to tell the difference between:
- side effects caused by Aptivus
- side effects caused by the other medicines you are also taking
- complications of HIV infection.

For this reason it is very important that you tell your doctor about any changes in your health. 

Serious side effects associated with Aptivus:

- Abnormal liver function
- Hepatitis and fatty liver
- Liver failure. This can lead to death 
- Increased blood levels of bilirubin (a breakdown product of haemoglobin)
You should inform your doctor if you experience:
- Loss of appetite
- Nausea (upset stomach)



92

- Vomiting and/or jaundice
which may be symptoms of abnormal liver function

- Bleeding
- *Bleeding in the brain. This can lead to permanent disability or death, and has 

occurred in some patients treated with Aptivus in clinical trials. In the majority of 
these patients the bleeding may have had other causes. For example they had other 
medical conditions or were receiving other medicine that may have caused the 
bleeding.

Possible side effects:

Very common: may affect more than 1 in 10 people
- Diarrhoea 
- Nausea (upset stomach)

Common: may affect up to 1 in 10 people
- Vomiting
- Abdominal pain (tummy pain)
- Flatulence (when you break wind more often)
- Tiredness
- Headache
- Mild rashes e.g. with hives or with flat or raised small red spots
- Increases in blood lipid (fat) levels
- Dyspepsia

Uncommon: may affect up to 1 in 100 people
- Reduction in red and white blood cells
- Reduction in blood platelets
- Allergic (hypersensitivity) reactions
- Decreased appetite
- Diabetes
- Increased blood sugar
- Increased blood levels of cholesterol
- Sleeplessness and other sleep disorders
- Sleepiness
- Dizziness
- Numbness and/or tingling and/or pain in the feet or hands
- Breathing difficulties
- Heartburn
- Inflammation of the pancreas
- Skin inflammation
- Itching

- Muscle cramp
- Muscle pain
- Kidney disease
- Flu like symptoms (feeling unwell)
- Fever
- Weight loss
- Increased blood levels of the pancreas enzyme amylase
- Increases in liver enzyme activity
- Hepatitis with liver cell damage due to influence of a toxin

Rare: may affect up to 1 in 1,000 people
- Liver failure (including fatal outcome)
- Hepatitis
- Fatty liver



93

- Increased blood levels of bilirubin (a breakdown product of haemoglobin)
- Dehydration (when your body does not have enough water)
- Thinning of the face
- Bleeding in the brain* (see above)
- Increased blood levels of the pancreas enzyme lipase

Further information on possible side effects related to combination antiretroviral treatment:
- Bleeding

- Increased bleeding. If you have haemophilia type A and B, you may experience 
increased bleeding. This may be in the skin or joints. If you suffer increased bleeding 
you should see your doctor immediately. 

Muscle disorders 
There have been reports of muscle pain, tenderness or weakness. These occur particularly when 
Aptivus or other protease inhibitors are taken together with nucleoside analogues. Rarely these muscle 
disorders have been serious, involving breakdown of muscle tissue (rhabdomyolysis).

Additional side effects in children and adolescents
The most common side effects were generally similar to those described in adults. Vomiting, rash and 
fever were observed more frequently in children than in adults.

Reporting of side effects
If you get any side effects, please talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Aptivus

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle after EXP. The expiry date 
refers to the last day of that month.

Store in a refrigerator (2°C to 8°C). Once the bottle is opened the contents must be used within 60 
days (stored below 25°C). You should write the date of opening the bottle on the label and/or outer 
carton. 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 

6. Contents of the pack and other information

What Aptivus contains
- The active substance is tipranavir. Each capsule contains 250 mg tipranavir.

- The other ingredients are macrogolglycerol ricinoleate, ethanol (alcohol), mono/diglycerides 
of caprylic/capric acid, propylene glycol, purified water, trometamol and propyl gallate. The 
capsule shell contains gelatin, red iron oxide, propylene glycol, purified water, ‘sorbitol 
special-glycerin blend’ (d-sorbitol, 1,4 sorbitan, mannitol and glycerin) and titanium dioxide. 
The black printing ink contains propylene glycol, black iron oxide, polyvinyl acetate 
phthalate, macrogol and ammonium hydroxide.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


94

What Aptivus looks like and contents of the pack
Aptivus soft capsules are pink coloured, oblong soft gelatin capsules with a black print imprint of 
‘TPV 250’. Each Aptivus capsule contains 250 mg of the active substance tipranavir. Aptivus is 
supplied in bottles containing 120 capsules. 

Marketing Authorisation Holder 

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany



95

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG 
Lietuvos filialas
Tel.: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG 
Magyarországi Fióktelepe
Tel.: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel.: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG, 
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG,
organizačná zložka
Tel: +421 2 5810 1211



96

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB 
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in {MM/YYYY}

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.



97

Package leaflet: Information for the user

Aptivus 100 mg/ml oral solution
tipranavir

Read all of this leaflet carefully before your child starts taking this medicine because it contains 
important information for your child.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, please ask your child’s doctor or pharmacist.
- This medicine has been prescribed for your child only. Do not pass it on to others. It may harm 

them, even if their signs of illness are the same as your child’s.
- If your child gets any side effects, talk to your child’s doctor or pharmacist. This includes any 

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What Aptivus is and what it is used for
2. What you need to know before your child takes Aptivus
3. How to take Aptivus
4. Possible side effects
5. How to store Aptivus
6. Contents of the pack and other information

1. What Aptivus is and what it is used for

Aptivus contains the active substance tipranavir. It belongs to a group of medicines called protease 
inhibitors and is used in the treatment of Human Immunodeficiency Virus (HIV) infection. It blocks 
an enzyme called protease that is involved in the reproduction of HIV. When the enzyme is blocked, 
the virus does not reproduce normally, slowing down the infection. Your child must take Aptivus
together with:

 low dose ritonavir (this helps Aptivus to reach a high enough level in your child’s blood)
 other HIV medicines. Your child’s doctor, together with you, will decide which other medicines 

your child should take. This will depend on, for example:
 which other medicines your child has already taken for HIV
 which medicines your child’s HIV is resistant to. If your child’s HIV is resistant to 

some HIV medicines, this means that the medicine will not work so well, or will not 
work at all.

Aptivus is specifically used for the treatment of HIV which is resistant to most other protease 
inhibitors. Before starting treatment, your child’s doctor will have taken blood samples to test the 
resistance of your child’s HIV. These tests will have confirmed that the HIV in your child’s blood is 
resistant to most other protease inhibitors. Aptivus treatment is therefore appropriate for your child. 
Your child should not use Aptivus if they have never received antiretroviral therapy or have other 
antiretroviral options available.

Aptivus oral solution is indicated for:
 children from 2 to 12 years of age 



98

2. What you need to know before your child takes Aptivus

Your child must take Aptivus in combination with low dose ritonavir and other antiretroviral 
medicines. It is therefore important that you know about these medicines too. You should 
therefore carefully read the Package Leaflets of ritonavir and your child’s other antiretroviral
medicines. If you have any further questions about ritonavir or the other medicines your child is 
prescribed, please ask your child’s doctor or pharmacist.

Do not give Aptivus
- if your child is allergic to tipranavir or any of the other ingredients of this medicine (listed in 

section 6)
- if your child has moderate to severe liver problems. Your child’s doctor will take a blood 

sample to test how well your child’s liver is working (your child’s liver function). Depending on 
your child’s liver function they may have to delay or stop Aptivus treatment

- if your child is currently taking products containing:
- rifampicin (used to treat tuberculosis)
- cisapride (used to treat stomach problems)
- pimozide or sertindole (used to treat schizophrenia)
- quetiapine (used to treat schizophrenia, bipolar disorder and major depressive 

disorder)
- lurasidone (used to treat schizophrenia)
- triazolam or oral midazolam (taken by mouth). These medicines are used to treat 

anxiety or sleep disorders
- ergot derivatives (used to treat headaches)
- astemizole or terfenadine (used to treat allergies or hay fever)
- simvastatin or lovastatin (used to lower blood cholesterol)
- amiodarone, bepridil, flecainide, propafenone or quinidine (used to treat heart 

disorders)
- metoprolol (used to treat heart failure)
- alfuzosin and sildenafil (when used to treat a rare blood vessel disorder characterized 

by increased pressure in the pulmonary artery)
- colchicine (when used to treat gout flares in patients with kidney or liver disease).

Your child must not take products containing St John’s wort (a herbal remedy for depression). This 
may stop Aptivus from working properly.

Warnings and precautions
Talk to your child’s doctor or pharmacist before giving Aptivus to your child.

Tell your child’s doctor if they have:
- type A or B haemophilia
- diabetes
- liver disease.

If your child has:
- high liver function tests results
- hepatitis B or C infection 
your child is at increased risk of severe and potentially fatal liver damage while taking Aptivus. Your 
child’s doctor will monitor their liver function by blood tests before and during Aptivus treatment. If 
your child has liver disease or hepatitis, their doctor will decide if they need additional testing. You 
should inform your child’s doctor as soon as possible if you notice your child has the signs or 
symptoms of hepatitis:
- fever
- malaise (feeling generally unwell)
- nausea (upset stomach)
- vomiting
- abdominal pain



99

- tiredness
- jaundice (yellowing of the skin or the eyeballs)

Aptivus is not a cure for HIV infection:
You should know that your child may continue to develop infections and other illnesses associated 
with HIV disease. You should therefore remain in regular contact with your child’s doctor. Your child 
can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy. Discuss with your child’s doctor the precautions needed to avoid infecting other 
people.

Rash:
Mild to moderate rash, including:
- hives
- rash with flat or raised small red spots
- sensitivity to the sun 
have been reported in approximately 1 in 10 patients receiving Aptivus. Some patients who developed 
rash also had:
- joint pain or stiffness
- throat tightness
- generalized itching

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs 
and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is 
started. It is believed that these symptoms are due to an improvement in the body’s immune response, 
enabling the body to fight infections that may have been present with no obvious symptoms. If you 
notice any symptoms of infection (for example fever, enlarged lymph nodes), please inform your 
child’s doctor immediately.

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after your child starts taking medicines for 
the treatment of your child’s HIV infection. Autoimmune disorders may occur many months after the 
start of treatment. If you notice any symptoms of infection or other symptoms such as muscle 
weakness, weakness beginning in the hands and feet and moving up towards the trunk of the body, 
palpitations, tremor or hyperactivity, please inform your child’s doctor immediately to seek necessary 
treatment.

Tell your child’s doctor if your child experiences fainting or a sensation of abnormal heart beats. 
Aptivus in combination with low dose ritonavir may cause changes in your child’s heart rhythm and 
the electrical activity of your child’s heart. These changes may be seen on an ECG 
(electrocardiogram).

Bone problems: Some patients taking combination antiretroviral therapy may develop a bone disease 
called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe 
immunosuppression, higher body mass index, among others, may be some of the many risk factors for 
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the 
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your child’s doctor.

Children and adolescents
Aptivus should neither be used by children under 2 years of age nor by adolescents 12 years of age or 
older.

Aptivus oral solution contains vitamin E. Your child should not take any additional vitamin E 
supplements.



100

Other medicines and Aptivus
Tell your child’s doctor or pharmacist if your child is taking, has recently taken or might take any 
other medicines, including medicines obtained without a prescription.

This is very important. If your child takes other medicines at the same time as Aptivus and ritonavir, 
this can strengthen or weaken the effect of the medicines. These effects are called interactions, and can 
lead to serious side effects, or prevent proper control of other conditions your child may have.

Interactions with other HIV medicines:
- etravirine belongs to a class of HIV medicines called non-nucleoside reverse transcriptase 

inhibitors (NNRTIs). Taking Aptivus with etravirine is not recommended.

- abacavir and zidovudine. These belong to a class of HIV medicines called nucleoside reverse 
transcriptase inhibitors (NRTIs). Your child’s doctor will only prescribe them abacavir and 
zidovudine if they are unable to take other NRTIs. 

- didanosine: If your child is taking didanosine enteric coated tablets, they should take them at 
least two hours before or after Aptivus. 

- emtricitabine: If your child is taking emtricitabine your child’s kidney function should be 
checked before initiation of Aptivus.

- rilpivirine: If your child is taking rilpivirine, your child’s doctor will monitor your child closely.

- Protease Inhibitors (PIs): Taking Aptivus may cause large decreases in the blood levels of other 
HIV protease inhibitors. For example the protease inhibitors amprenavir, atazanavir, lopinavir 
and saquinavir will be decreased.
Taking Aptivus, with atazanavir, may cause the blood levels of Aptivus and ritonavir to increase 
a lot. 
Your child’s doctor will carefully consider whether to treat them with combinations of Aptivus
and protease inhibitors.

Other medicines with which Aptivus may interact include:
- oral contraceptives/hormone replacement therapy (HRT): If your child is taking the 

contraceptive pill to prevent pregnancy they should use an additional or different type of 
contraception (e.g. barrier contraception like condoms). Generally, it is not recommended to 
take Aptivus, with ritonavir, together with oral contraceptives or hormone replacement therapy 
(HRT). You should check with your child’s doctor if they do wish to continue taking oral 
contraceptives or HRT. If your child uses oral contraceptives or HRT they have an increased 
chance of developing a skin rash while taking Aptivus. If a rash occurs, it is usually mild to 
moderate. You should talk to your child’s doctor as they may need to temporarily stop taking 
either Aptivus or their oral contraceptives or HRT

- carbamazepine, phenobarbital and phenytoin (used to treat epilepsy). These may decrease the 
effectiveness of Aptivus.

- sildenafil, vardenafil, tadalafil (medicines used to produce and maintain an erection). The effects 
of sildenafil and vardenafil are likely to be increased if taken with Aptivus. Tadalafil should not 
be prescribed until Aptivus has been taken  for 7 days or more.

- omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole (proton pump inhibitors 
used to reduce the gastric acid production)

- metronidazole (used to treat infections) 
- disulfiram (used to treat alcohol dependence)
- buprenorphine/naloxone (medicines used to treat severe pain)
- cyclosporin, tacrolimus, sirolimus (used to prevent organ rejection (to suppress the immune 

system))
- warfarin (used to treat and prevent thrombosis)



101

- digoxin (used to treat heart arrhythmias and heart failure)
- antifungal medications including fluconazole, itraconazole, ketoconazole or voriconazole

The following medicines are not recommended:
- fluticasone (used to treat asthma)
- atorvastatin (used to lower blood cholesterol)
- salmeterol (used to achieve long-term asthma control, bronchospasm prevention with COPD)
- bosentan (used to treat pulmonary artery hypertension)
- halofantrine or lumefantrine (used to treat malaria)
- tolterodine (used to treat overactive bladder (with symptoms of urinary frequency, urgency, or 

urge incontinence))
- boceprevir and telaprevir (used to treat hepatitis C)
- cobicistat and products containing cobicistat (used to increase effectiveness of HIV medicines).

Aptivus may lead to a loss of effectiveness of some medicines including:
- methadone, meperidine (pethidine), used as morphine substitutes

Your child’s doctor may have to increase or decrease the dose of other medicines which they take 
together with Aptivus. Examples include:
- rifabutin and clarithromycin (antibiotics)
- theophylline (used to treat asthma) 
- desipramine, trazodone and bupropion (used to treat depression; bupropion is also used for 

smoking cessation)
- midazolam (when given by injection); midazolam is a sedative used to treat anxiety and to help 

your child sleep
- rosuvastatin or pravastatin (used to lower blood cholesterol)
- colchicine (used to treat gout flares with normal kidney and liver function)
- raltegravir (used to treat HIV infection)
- dolutegravir (used to treat HIV infection)

If your child takes aluminium- and magnesium-based antacid (used to treat dyspepsia/ 
gastrooesophageal reflux), the time interval between Aptivus and antacid should be at least two hours.

Tell your child’s doctor if your child receives medicines such as blood-thinning agents, or if your child 
is taking vitamin E. Your child’s doctor may wish to consider certain precautionary measures in such 
circumstances.

Pregnancy, breast-feeding and fertility
If your child is pregnant or breast-feeding, you think your child may be pregnant or is planning to have 
a baby, ask your child’s doctor or pharmacist for advice before giving this medicine. It is not known 
whether Aptivus may be used safely during pregnancy. Your child must not breast-feed the baby 
because it is possible that the baby can become HIV-infected through the breast milk. See also Section 
2, under “Oral contraceptives/hormone replacement therapy (HRT)”.

Driving and using machines
Some of the side effects of Aptivus may affect your child’s ability to drive or operate machinery (e.g. 
dizziness and sleepiness). If affected, your child should not drive or operate machinery. 

3. How to take Aptivus

Always give your child this medicine exactly as the doctor has advised. Check with your child’s 
doctor or pharmacist if you are not sure. Your child must take Aptivus together with ritonavir. 

Aptivus oral solution should be taken with food.



102

The dose for children, aged 2 to 12 years, will be calculated by the doctor. This will be based on the 
child’s body surface area in metres squared. The dose for children should not exceed 5 ml (500 mg) 
twice a day. Be sure your child’s doctor clearly informs you what the correct dose for your child 
should be. You should measure the exact dose using the supplied measuring syringe and adapter, as 
follows:

1. Check that the oral solution is clear (see below). 
2. Open the bottle by pressing down on the cap and turning it in an anti-clockwise direction.
3. Remove the syringe cap covering the tip of the oral syringe (the cap will not be attached if this 

is the first time you are using the syringe).
4. Insert the oral syringe into the adapter located in the neck of the bottle. Make sure the oral 

syringe is tightly inserted. The maximum volume you can withdraw at one time is 5 ml 
(equivalent to 500 mg tipranavir), which is the maximum single dose for a child with BSA
(Calculated body surface area) > 1.33 m2

5. Turn the bottle upside down and gently withdraw the required amount of Aptivus oral solution.
6. Gently empty Aptivus oral solution from the syringe into your child’s mouth.
7. After use of the oral syringe, replace the syringe cap.

Before giving Aptivus you should check that the oral solution is clear. Crystals may be seen as a 
paper-thin layer at the bottom of the bottle when it is stored upright. There may be other particles at 
the bottom of the bottle. A small amount of crystals does not affect the strength or safety of your 
child’s medicine.  

You should return the bottle to your child’s pharmacist or doctor for a replacement as soon as possible 
if:
- there is more than a thin layer of crystals at the bottom of the bottle, or
- you are uncertain about the amount of crystals you see or
- any other particles are visible. 
Until you exchange the bottle, please continue to give your child their usual doses of Aptivus oral 
solution.

Your child will always have to take Aptivus in combination with other antiretroviral medicines. You 
should follow the instructions for these medicines within the supplied Package Leaflets.

Your child should continue to take Aptivus for as long as your child’s doctor tells him/her. At the age 
of 12 years, children treated with Aptivus should be switched from the oral solution to the capsules.

If your child takes more Aptivus than he/she should
Inform your child’s doctor as soon as possible if they take more than the prescribed dose of Aptivus.

If your child forgets to take Aptivus
If your child misses a dose of Aptivus or ritonavir by more than 5 hours, wait and then give the next 
dose of Aptivus and ritonavir at the regularly scheduled time. If your child misses a dose of Aptivus
and/or ritonavir by less than 5 hours, give the missed dose immediately. Then give the next dose of 
Aptivus and ritonavir at the regularly scheduled time.

Do not give a double dose to make up for a forgotten dose.

If your child stops taking Aptivus
It has been shown that taking all doses at the appropriate times:
- greatly increases the effectiveness of your child’s combination antiretroviral medicines
- reduces the chances of your child’s HIV becoming resistant to his/her antiretroviral medicines. 

Therefore, it is important that your child continues taking Aptivus correctly, as described above. Your 
child must NOT stop taking Aptivus unless your child’s doctor instructs to do so.

If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist.



103

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your child’s doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them. It may be 
difficult to tell the difference between:
- side effects caused by Aptivus
- side effects caused by the other medicines your child is also taking
- complications of HIV infection. 

For this reason it is very important that you tell your child’s doctor about any changes in their health. 

Serious side effects associated with Aptivus:

- Abnormal liver function
- Hepatitis and fatty liver 
- Liver failure. This can lead to death 
- Increased blood levels of bilirubin (a breakdown product of haemoglobin)
You should inform your child’s doctor if they experience:
- Loss of appetite
- Nausea (upset stomach)
- Vomiting and/or jaundice
which may be symptoms of abnormal liver function

- Bleeding
- * Bleeding in the brain. This can lead to permanent disability or death, and has 

occurred in some patients treated with Aptivus in clinical trials. In the majority of 
these patients the bleeding may have had other causes. For example they had other 
medical conditions or were receiving other medicine that may have caused the 
bleeding.

Possible side effects:

Very common: may affect more than 1 in 10 people
- Diarrhoea 
- Nausea (upset stomach)

Common: may affect up to 1 in 10 people
- Vomiting
- Abdominal pain (tummy pain)
- Flatulence (breaking wind more often)
- Tiredness
- Headache
- Mild rashes e.g. with hives or with flat or raised small red spots
- Increases in blood lipid (fat) levels
- Dyspepsia

Uncommon: may affect up to 1 in 100 people
- Reduction in red and white blood cells
- Reduction in blood platelets
- Allergic (hypersensitivity) reactions
- Decreased appetite
- Diabetes
- Increased blood sugar



104

- Increased blood levels of cholesterol
- Sleeplessness and other sleep disorders
- Sleepiness
- Dizziness
- Numbness and/or tingling and/or pain in the feet or hands
- Breathing difficulties
- Heartburn
- Inflammation of the pancreas
- Skin inflammation
- Itching
- Muscle cramp
- Muscle pain
- Kidney disease
- Flu like symptoms (feeling unwell)
- Fever
- Weight loss
- Increased blood levels of the pancreas enzyme amylase
- Increases in liver enzyme activity
- Hepatitis with liver cell damage due to influence of a toxin

Rare: may affect up to 1 in 1,000 people
- Liver failure (including fatal outcome)
- Hepatitis
- Fatty liver
- Increased blood levels of bilirubin (a breakdown product of haemoglobin)
- Dehydration (when the body does not have enough water)
- Thinning of the face
- Bleeding in the brain* (see above)
- Increased blood levels of the pancreas enzyme lipase

Further information on possible side effects related to combination antiretroviral treatment:
- Bleeding

- Increased bleeding. If your child has haemophilia type A and B, they may experience 
increased bleeding. This may be in the skin or joints. If your child suffers increased 
bleeding you should see your child’s doctor immediately. 

Muscle disorders 
There have been reports of muscle pain, tenderness or weakness. These occur particularly when 
Aptivus or other protease inhibitors are taken together with nucleoside analogues. Rarely these muscle 
disorders have been serious, involving breakdown of muscle tissue (rhabdomyolysis).

Additional side effects in children and adolescents
The most common side effects were generally similar to those described in adults. Vomiting, rash and 
fever were observed more frequently in children than in adults.

Reporting of side effects
If your child gets any side effects, please talk to your child’s doctor or pharmacist. This includes any 

possible side effects not listed in this leaflet. You can also report side effects directly via the national 

reporting system listed in Appendix V. By reporting side effects you can help provide more 

information on the safety of this medicine.

5. How to store Aptivus

Keep this medicine out of the sight and reach of children.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


105

Do not use this medicine after the expiry date which is stated on the bottle after EXP. The expiry date 
refers to the last day of that month.

Store between 15°C and 25ºC. Do not refrigerate or freeze. Once the bottle is opened your child 
should use the medicine within 60 days. You should write the date of opening the bottle on the label 
and/or outer carton. Keep the container in the outer carton.
If you notice more than a thin layer of crystals at the bottom of the bottle you should:
- give the next dose
- return the bottle to the pharmacist or doctor as soon as possible for a fresh supply.

Do not throw away any medicines via wastewater or household waste. Ask your child’s pharmacist 
how to throw away medicines you no longer use. These measures will help protect the environment. 

6. Contents of the pack and other information

What Aptivus contains
- The active substance is tipranavir. Each ml contains 100 mg tipranavir.
- The other ingredients are macrogol, vitamin E polyethylene glycol succinate, purified water, 

propylene glycol, mono/diglycerides of caprylic/capric acid, sucralose, ascorbic acid, Butter 
Mint and Butter Toffee flavourings.

What Aptivus looks like and contents of the pack
Aptivus oral solution is a clear yellow liquid. 

Aptivus oral solution is supplied in amber glass bottles containing 95 ml of oral solution. A 5 ml oral 
syringe and adapter is supplied for dosing.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer 

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany



106

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG 
Lietuvos filialas
Tel.: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG 
Magyarországi Fióktelepe
Tel.: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel.: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG, 
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG,
organizačná zložka
Tel: +421 2 5810 1211



107

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB 
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last approved in {MM/YYYY}

Detailed information on this medicine is available on the European Medicines Agency (EMA) web 
site: http://www.ema.europa.eu.

http://www.emea.europa.eu

	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET