When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Product
Aptivus 250mg soft capsules
Changed Section
Section 4.2 (Posology and method of administration)
Details of Change
The following text has been added:
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. Changed Section Section 4.4 (Special Warnings and Precautions for Use) Details of Change Some minor rewording regarding the co-administration of APTIVUS with: atorvastatin omeprazole and other proton pump inhibitors.
Section 4.4 (Special Warnings and Precautions for Use)
Some minor rewording regarding the co-administration of APTIVUS with:
atorvastatin
omeprazole and other proton pump inhibitors.
Section 4.5 (Interactions with other medicinal products)
Complete rewrite into tabular format.
Section 10 (Date of revision of the text)
November 2009
Section 4.1
Now contains the following information:
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.
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 (see section 5.1).
Section 4.2
Adults and adolescents from 12 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.
Children under 12 years of age:
No data are available on the efficacy and safety of APTIVUS capsules in children under 12 years of age. 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 SPC for further details).
APTIVUS is not recommended for use in children under 2 years of age due to insufficient data on safety and efficacy.
Section 4.4
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).
Rash
In the paediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was higher than in adult patients.
Section 4.8
Paediatrics
In an open-label, dose-finding study of APTIVUS 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 pediatric 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
Rash2
Insomnia
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 pruitic, and urticaria
Section 5.1
Paediatric patients
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 APTIVUS/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)
330 (12 – 593)
% ≤ 200
Baseline % CD4+ cells
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
* AIDS defining illness
Key efficacy results at 48 weeks for patients 12 – 18 years of age who took capsule
Endpoint
Result
Number of patients
Primary efficacy endpoint:
% with VL < 400
Median change from baseline
in log10 HIV-1 RNA (copies/mL)
-0.79
in CD4+ cell count (cells/mm3)
39
in % CD4+ cells
3%
Details of Main Changes
Section 4.5 - Now includes a table with information on the interaction of Aptivus with buprenorphine/naloxone
Section 4.5: Co-administration of Aptivus with low-dose ritonavir and buproprion may result in decreased buproprion Cmax and AUC0-12h.
Section 4.3 - Combination of rifampicin with Aptivus and low-dose ritonavir is contraindicated
Section 4.5 - Rifampicin causes profound decreases in concentrations of other protease inhibitors which can
result in virological failure and resistance development.
Change to section 4.4 Special warnings and precautions for use
Change to section 5.3 Preclinical safety data
Main Change
Section 4.4 Special warnings and precautions for use:
Information on interactions with Vitamin E has been added. It is not recommended to co-administer more than 1200 IU vitamin E per day.
Aptivus co-administered with low dose ritonavir decreases the plasma concentrations of the proton pump inhibitors omeprazole and esomeprazole.
Section 4.5 Interaction with other medicinal products and other forms of interaction:
Further information on the interaction of aptivus and low-dose ritonavir with omeprazole is included.
Section 5.3 has been updated to include information regarding in vitro inhibition of platelet binding and thromboxane A2 binding.
Section 4.2 (Posology and method of administration) contains new information regarding use in the elderly as follows: “Clinical studies of Aptivus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently to younger subjects.”
Section 4.4 (special warnings and special precautions for use) includes a new sentence to note that Aptivus soft capsules contain a small amount of alcohol.
Section 4.5 (Interaction with other medicinal products and other forms of interaction) has been updated to include new data on efavirenz, nevirapine, taladafil. In summary; a drug interaction study with efavirenz showed no evidence of a clinically relevant interaction between the efavirenz and Aptivus co-administered with low dose ritonavir. Data from a phase IIa study suggests no significant interaction with nevirapine and it is now advised that no dose adjustments are necessary. A pharmacokinetic study showed Aptivus/ritonavir increased taladafil exposure at the first dose but did not increase taladafil exposure at steady state. It is recommended to prescribe taladafil after at least 7 days of Aptivus/ritonavir dosing.
Orally administered midazolam and metoprolol have been added to the list of CYP3A cleared drugs and CYP 2D6 cleared drugs, respectively. Co-administration of Aptivus with drugs which are highly dependent on these pathways for clearance is contra-indicated.
Section 4.4 has been updated with the following information regarding co-administration of anti-consultants: " 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.
Section 4.5 has been updated with the following information: "A cocktail study was conducted in 16 healthy volunteers with twice daily Aptivus/ritonavir 500/200 mg capsules 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 3A$ (midazolam) and P-glycoprotein (Pgp) (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. Pgp activity is significantly inhibited after the first dose, but there was a slight induction at steady state."
Information regarding co-administration with digoxin has been added as follows: "Aptivus, co-administered with low dose ritonavir, may double the exposure of orally administered digoxin at the first dose, whilst the net effect at steady state may rather consist in a slight decrease in digoxin exposure. Monitoring of digoxin serum concentrations is recommended until steady state has been obtained"
Information on midazolam has been included in this section, and states that concomitant use of Aptivus/ritonavir ad oral midazolam is contra-indicated, and states "If Aptivus/ritonavir is administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be instituted and dosage adjustment considered".
There is also additional information on interactions with carbemazepine (see new special warning above). Furthermore information relation to an interaction with theophylline has been updated and it is now advised that theophylline plasma concentrations should be monitored during the first two weeks or co-administration with Aptivus/ritonavir and the theophylline dose should be increased as need.
Section 5.1 has bee updated to include information on the correlation between baseline resistance and virological response at 48 weeks.
Section 4.4 (Special warnings and special precautions for use) has been updated with regard to the advice for liver function monitoring, and the advice not to use in treatment naive patients has been reinforced with additional information regarding an increased risk of significant transaminase elevations when Aptivus/ritonavir combination was used in this patient group. In addition, information regarding the risk of osteonecrosis in patients with advanced HIV-disease and/or long term exposure to combination antiretroviral therapy has been added and this section now also advises that in in vitro experiments tipranavir was observed to inhibit human platelets aggregation at levels consistent with exposures observed in patients receiving Aptivus/ritonavir.
Section 4.8 (Undesirable effects) has been updated with information from the 48 week analyses of the pivotal RESIST-1 and RESIST-2 clinical trials. Previously only data for the 24 week analyses was available and thus the incidence rates of some adverse events have been updated with the 48 week data. Hyperbilirubinaemia (rare) has been added to the list of adverse events and this section now also provides information regarding the risk of osteonecrosis in patients with advanced HIV-disease and/or long term exposure to combination antiretroviral therapy.
Section 5.1 (Pharmacodynamic properties) has been updated with data from the 48 week analyses of the pivotal RESIST-1 and RESIST-2 clinical trials.
Section 4.5 has been updated with the following information regarding concomitant use of trazodone: "In a pharmacokinetic study performed in healthy volunteers, concomitant use of low dose ritonavir (200 mg twice daily) with 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/ritonavir might cause a larger increase in trazodone exposure. The combination should be used with caution and a lower dose of trazodone should be considered."
Section 5.1 has been updated with information regarding the in vitro antiviral activity of Aptivus.
Section 4.8 (undesirable effects) has been updated with information regarding increased risk of bleeding and the occurrence of fatal and non fatal intracranial haemorrhage, as follows:
“Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving APTIVUS, many of whom had other medical conditions or were receiving concomitant medications 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.”
Section 4.4 (Special warnings and special precautions for use) has been updated to include information regarding bleeding, previously only stated in Section 4.8, and intracranial haemorrhage, as above, and also includes the following statement:
“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 medications known to increase the risk of bleeding such as antiplatelet agents or anticoagulants.”
Section 4.5 (Interactions with other medicinal products and other forms of interaction) has been updated with new information regarding interactions with methadone and atazanavir:
“Narcotic analgesics (Methadone/Meperidine): Co-administration of APTIVUS and low dose ritonavir with single dose methadone was demonstrated to decrease methadone pharmacokinetic parameters (AUC0-24h ratio of 0.47 with 90% CI [0.44; 0.51] and Cmax ratio of 0.45 with 90% CI [0.41; 0.49]), in a study conducted in fasted healthy subjects. Therefore in such cases, patients should be monitored for opiate withdrawal syndrome. Dosage of methadone may need to be increased.”
And:
“Co-administration of Tipranavir/ritonavir and Atazanavir/ritonavir:
In a study performed in healthy volunteers co-administration of atazanavir 300 mg with TPV/r 500/100 mg bid resulted on one hand in a marked increase of Tipranavir exposure (notably Cp12h ratio of 1.75 with 90% CI [1.39-2.20]) and ritonavir exposure (AUC ratio of 1.51 with 90% CI [1.24-1.83] and Cmax ratio of 1.38 with 90% CI [1.13-1.67]) associated with a risk of over-toxicity and on the other hand on a marked decrease of atazanavir exposure associated with a risk of loss of efficacy (AUC0-24h ratio of 0.32 with 90% CI [0.29-0.36], Cmax ratio of 0.43 with 90% CI [0.38-0.50] and Cp24h ratio of 0.19 with 90% CI [0.15-0.24]).
“Consequently, this co-administration 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.”