Chemical formula: C₂₅H₃₆N₃O₉PS Molecular mass: 585.607 g/mol PubChem compound: 131536
Fosamprenavir interacts in the following cases:
Interaction – Geometric mean change (%) (Possible mechanism):
Sildenafil/Vardenafil/Tadalafil: No drug interaction studies.
PDE5 inhibitors: ↑ expected
(CYP3A4 inhibition by FPV/RTV)
Recommendation concerning co-administration: Concomitant use is not recommended. It may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, visual changes and priapism. Patients should be warned about these possible side effects when using PDE5 inhibitors with fosamprenavir/ritonavir. Note that coadministration of fosamprenavir with low dose ritonavir with sildenafil used for the treatment of pulmonary arterial hypertension is contraindicated.
For adults with moderate hepatic impairment (Child-Pugh score: 7-9) the recommended dose is 450 mg fosamprenavir twice daily with 100 mg ritonavir once daily. This adjusted dose has not been evaluated in a clinical study and has been derived from extrapolation. As it is not possible to achieve this fosamprenavir dose using the tablet formulation, these patients should be treated with fosamprenavir oral suspension.
Overall, even with these dose adjustments for adults with hepatic impairment, some patients may have higher or lower than anticipated amprenavir and/or ritonavir plasma concentrations as compared to patients with normal hepatic function, due to increased inter-patient variability, therefore close monitoring of safety and virologic response is warranted.
For adults with severe hepatic impairment (Child-Pugh score: 10-15) fosamprenavir should be used with caution and at a reduced dose of 300 mg fosamprenavir twice daily with 100 mg ritonavir once daily. As it is not possible to achieve this fosamprenavir dose using the tablet formulation, these patients should be treated with fosamprenavir oral suspension.
Overall, even with these dose adjustments for adults with hepatic impairment, some patients may have higher or lower than anticipated amprenavir and/or ritonavir plasma concentrations as compared to patients with normal hepatic function, due to increased inter-patient variability, therefore close monitoring of safety and virologic response is warranted.
Interaction – Geometric mean change (%) (Possible mechanism):
Desipramine/Nortriptyline: No drug interaction studies.
Tricyclic antidepressant: ↑ expected
(Mild CYP2D6 inhibition by RTV)
Recommendation concerning co-administration: Careful monitoring of the therapeutic and adverse reactions of tricyclic antidepressants is recommended.
Interaction – Geometric mean change (%) (Possible mechanism):
Atorvastatin 10 mg once daily for 4 days:
(CYP3A4 inhibition by FPV/RTV)
Recommendation concerning co-administration: Doses of atorvastatin no greater than 20 mg/day should be administered, with careful monitoring for atorvastatin toxicity.
Interaction – Geometric mean change (%) (Possible mechanism):
Phenobarbital/Carbamazepine: No drug interaction studies.
Amprenavir: ↓ expected
(Modest CYP3A4 induction)
Recommendation concerning co-administration: Use with caution.
Interaction – Geometric mean change (%) (Possible mechanism):
Cyclosporin/Rapamycin/Tacrolimus: No drug interaction studies.
Cyclosporin: ↑ expected
Rapamycin: ↑ expected
Tacrolimus: ↑ expected
(CYP3A4 inhibition by FPV/RTV)
Recommendation concerning co-administration: Frequent therapeutic concentration monitoring of immunosuppressant levels is recommended until levels have stabilised.
Interaction – Geometric mean change (%) (Possible mechanism):
Clarithromycin: moderate ↑ expected
(CYP3A4 inhibition)
Study performed with amprenavir.
No FPV/RTV drug interaction studies.
Recommendation concerning co-administration: Use with caution.
Interaction – Geometric mean change (%) (Possible mechanism):
Examples of antineoplastic agents:
dasatinib: ↑ expected
nilotinib: ↑ expected
ibrutinib: ↑ expected
vinblastine: ↑ expected
everolimus: ↑ expected
(CYP3A4 inhibition)
No FPV/RTV drug interaction studies.
Recommendation concerning co-administration: When antineoplastic agents that are metabolised by CYP3A are co-administered with fosamprenavir/ritonavir, plasma concentrations of these antineoplastic medications may be increased and could increase the risk of adverse events usually associated with these antineoplastic agents. In case of concomitant administration with antineoplastic agents metabolized by CYP3A, please refer to the relevant product information for these medications.
Interaction – Geometric mean change (%) (Possible mechanism):
Dolutegravir 50 mg once daily:
Dolutegravir
Recommendation concerning co-administration: No dosage adjustment of fosamprenavir or dolutegravir is recommended based on observed exposure-response relationships of clinical data. Caution is warranted and close monitoring is recommended when this combination is given in integrase inhibitor-resistant patients.
Interaction – Geometric mean change (%) (Possible mechanism):
Erythromycin: ↑ expected
(CYP3A4 inhibition by FPV/RTV)
No drug interaction studies.
Recommendation concerning co-administration: Use with caution.
Interaction – Geometric mean change (%) (Possible mechanism):
Ethinyl estradiol 0.035 mg/norethisterone 0.5 mg once daily:
(CYP3A4 induction by FPV/RTV)
Amprenavir
* compared to historical data
* compared to historical data
Clinically significant hepatic transaminase elevations occurred in some subjects.
Recommendation concerning co-administration: Alternative non-hormonal methods of contraception are recommended for women of childbearing potential.
Interaction – Geometric mean change (%) (Possible mechanism):
Etravirine (Study conducted in 8 patients):
a Comparison based on historic control.
Recommendation concerning co-administration: Fosamprenavir may require dose reduction (using oral suspension).
Interaction – Geometric mean change (%) (Possible mechanism):
Fluticasone propionate 50 µg intranasal 4 times daily) for 7 days (Ritonavir 100 mg capsules twice daily for 7 days):
Fluticasone propionate: ↑
Intrinsic cortisol levels: ↓86%
The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.
Greater effects may be expected when fluticasone propionate is inhaled.
(CYP3A4 inhibition by FPV/RTV)
Recommendation concerning co-administration: Concomitant use is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. A dose reduction of the glucocorticoid with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone) should be considered. In case of withdrawal of glucocorticoids, progressive dose reduction may have to be performed over a longer period.
Interaction – Geometric mean change (%) (Possible mechanism):
Halofantrine: No drug interaction studies.
Halofantrine: ↑ expected
(CYP3A4 inhibition by FPV/RTV)
Recommendation concerning co-administration: Concomitant use is not recommended. It may cause serious adverse reactions.
Interaction – Geometric mean change (%) (Possible mechanism):
Ketoconazole 200 mg once daily for four days:
Itraconazole: No drug interaction studies.
Itraconazole: ↑ expected
(CYP3A4 inhibition by FPV/RTV)
Recommendation concerning co-administration: High doses (>200 mg/day) of itraconazole are not recommended.
Interaction – Geometric mean change (%) (Possible mechanism):
Ketoconazole 200 mg once daily for four days:
Recommendation concerning co-administration: High doses (>200 mg/day) of ketoconazole are not recommended.
Interaction – Geometric mean change (%) (Possible mechanism):
Lidocaine (by systemic route): No drug interaction studies.
Lidocaine: ↑ expected
(CYP3A4 inhibition by FPV/RTV)
Recommendation concerning co-administration: Concomitant use is not recommended. It may cause serious adverse reactions.
Interaction – Geometric mean change (%) (Possible mechanism):
Lopinavir/ritonavir 400 mg/100 mg twice daily:
* compared to lopinavir/ritonavir 400 mg/100 mg twice daily
Lopinavir/ritonavir 533 mg/133 mg twice daily:
* compared to fosamprenavir/ritonavir 700 mg/100 mg twice daily
(Mixed CYP3A4 induction/inhibition, P-gp induction)
Recommendation concerning co-administration: Concomitant use is not recommended.
Interaction – Geometric mean change (%) (Possible mechanism):
Maraviroc 300 mg twice daily:
Recommendation concerning co-administration: Concomitant use is not recommended. Significant reductions in amprenavir Cmin observed may result in virological failure in patients.
Interaction – Geometric mean change (%) (Possible mechanism):
Methadone ≤200 mg once daily:
(CYP induction by FPV/RTV)
Recommendation concerning co-administration: The decrease of (R-) methadone (active enantiomer) is not expected to be clinically significant. As a precaution, patients should be monitored for withdrawal syndrome.
Interaction – Geometric mean change (%) (Possible mechanism):
No drug interaction studies.
Midazolam: ↑ expected (3-4 fold for parenteral midazolam)
Based on data with other protease inhibitors plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally.
(CYP3A4 inhibition by FPV/RTV)
Recommendation concerning co-administration:
Fosamprenavir/ritonavir should not be co-administered with orally administered midazolam, whereas caution should be used with co-administration of Telzir/ritonavir and parenteral midazolam.
If fosamprenavir/ritonavir is coadministered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Interaction – Geometric mean change (%) (Possible mechanism):
Paroxetine 20 mg once daily:
* compared to historical data
Mechanism unknown.
Recommendation concerning co-administration: Dose titration of paroxetine based on a clinical assessment of antidepressant response is recommended. Patients on stable dose of paroxetine who start treatment with fosamprenavir and ritonavir should be monitored for antidepressant response.
Use with caution.
No drug interaction studies.
Amprenavir: ↓ expected
(Modest CYP3A4 induction)
Interaction – Geometric mean change (%) (Possible mechanism):
Phenytoin 300 mg once daily:
(Modest induction of CYP3A4 by FPV/RTV)
Recommendation concerning co-administration: It is recommended that phenytoin plasma concentrations be monitored and phenytoin dose increased as appropriate.
Interaction – Geometric mean change (%) (Possible mechanism):
Raltegravir 400 mg twice daily:
Fasting state:
Fed state:
Recommendation concerning co-administration: Concomitant use is not recommended. Significant reductions in exposure and Cmin observed for both amprenavir and raltegravir (especially in fed conditions) may result in virological failure in patients.
Interaction – Geometric mean change (%) (Possible mechanism):
Rifabutin 150 mg every other day:
AUC(0-48): ↔*
* compared to rifabutin 300 mg once daily
Amprenavir exposure unchanged when compared to historical data.
(Mixed CYP3A4 induction/inhibition)
Recommendation concerning co-administration:
The increase of 25-O-desacetylrifabutin (active metabolite) could potentially lead to an increase of rifabutin related adverse events, notably uveitis.
A 75% reduction of the standard rifabutin dose (i.e. to 150 mg every other day) is recommended. Further dose reduction may be necessary.
Not recommended. Not studied.
Results from studies with other HIV protease inhibitors and simeprevir or daclatasvir, suggest that coadministration with fosamprenavir/ritonavir is likely to lead to increased plasma exposures of simeprevir or daclatasvir due to CYP3A4 enzyme inhibition.
Interaction – Geometric mean change (%) (Possible mechanism):
Warfarin/Other oral anticoagulants: No drug interaction studies.
Possible ↓ or ↑ of antithrombotic effect.
(Induction and/or inhibition of CYP2C9 by RTV)
Recommendation concerning co-administration: Reinforced monitoring of the International Normalised Ratio is recommended.
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 CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
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. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Most patients with mild or moderate rash can continue fosamprenavir. Appropriate antihistamines (e.g. cetirizine dihydrochloride) may reduce pruritus and hasten the resolution of rash. Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, were reported in less than 1% of patients included in the clinical development programme. Fosamprenavir should be permanently discontinued in case of severe rash, or in case of rash of moderate intensity with systemic or mucosal symptoms.
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 mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated andtreatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and can occur many months after initiation of treatment.
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In 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 pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered
There have been reports of increased bleeding including spontaneous skin haematomas and haemarthroses in haemophiliac patients type A and B treated with protease inhibitors (PIs). In some patients administration of factor VIII was necessary. 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 has not been elucidated. Haemophiliac patients should therefore be informed of the possibility of increased bleeding.
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
There is limited clinical experience (less than 300 pregnancy outcomes) from the use of fosamprenavir in pregnant women. Placental transfer of amprenavir has been shown to occur in humans.
In animal studies at systemic plasma exposures (AUC) to amprenavir lower than therapeutic exposure in patients treated with fosamprenavir, some developmental toxicity was observed. In view of the low exposure in reproductive toxicity studies, the potential developmental toxicity of fosamprenavir has not been fully determined.
Fosamprenavir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Amprenavir-related material was found in rat milk, but it is not known whether amprenavir is excreted in human milk. Rat pups exposed pre and post-natally to amprenavir and fosamprenavir showed developmental toxicity.
It is recommended that HIV-infected women must not breast-feed under any circumstances to avoid transmission of HIV.
No human data on the effect of fosamprenavir on fertility are available. In rats, there was no major effect on fertillty or reproductive performance with fosamprenavir.
No studies on the effects of fosamprenavir in combination with ritonavir on the ability to drive and use machines have been performed. The adverse reaction profile of fosamprenavir should be borne in mind when considering the patient’s ability to drive or operate machinery.
The adverse reaction profile was similar across all the respective adult studies: antiretroviral naïve patients (APV30002, ESS100732), protease inhibitor experienced (twice daily dosing, APV30003) patients. This is based on safety data from a total of 864 patients exposed to fosamprenavir/ritonavir in these three studies.
The most frequently (>5% of adult subjects treated) reported adverse reactions with fosamprenavir/ritonavir combination were gastrointestinal reactions (nausea, diarrhoea, abdominal pain and vomiting) and headache. Most adverse reactions associated with fosamprenavir/ritonavir combination therapies were mild to moderate in severity, early in onset and rarely treatment limiting. More serious adverse reactions such as serious skin rashes and hepatic transaminase elevations have also been reported (cf paragraph Description of selected adverse reactions).
Adverse reactions are listed by MedDRA system organ class and absolute frequency. Frequencies are defined as: 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) or Very rare (<1/10,000), or Not known.
Frequency categories for the reactions below have been based on clinical trials and postmarketing data.
Most of the adverse reactions below were reported from three large clinical studies in adults, where the adverse events were of at least moderate intensity (Grade 2 or more) occurring in at least 1% of patients and reported by investigators as being attributable to the medicinal products used in the studies.
Common: Headache, dizziness, oral paraesthesia
Very common: Diarrhoea
Common: Loose stools, nausea, vomiting, abdominal pain
Rare: Stevens Johnson syndrome
Uncommon: Angioedema
Common: Rash (see text below “rash/cutaneous reactions”)
Common: Fatigue
Very common: Blood cholesterol increased
Common: Blood triglycerides increased, Alanine aminotransferase increased, Aspartate aminotransferase increased, Lipase increased
Erythematous or maculopapular cutaneous eruptions, with or without pruritus, may occur during therapy. The rash generally will resolve spontaneously without the necessity of discontinuing treatment with the fosamprenavir with ritonavir.
Severe or life-threatening cases of rash, including Stevens-Johnson syndrome are rare. Fosamprenavir with ritonavir therapy should be definitively stopped in case of severe rash or in case of rash of mild or moderate intensity associated with systemic or mucosal signs.
Clinical chemistry abnormalities (Grade 3 or 4) potentially related to treatment with fosamprenavir with ritonavir and reported in greater than or equal to 1% of adult patients, included: increased ALT (common), AST (common), serum lipase (common) and triglycerides (common).
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
An increase in CPK, myalgia, myositis, and rarely, rhabdomyolysis, have been reported with protease inhibitors, more specifically in association with nucleoside analogues.
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) 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.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown.
The adverse reaction profile in children and adolescents is based on integrated safety data from two studies (APV29005 Week 24 data and APV20003 Week 168 data [final data]) in which 158 HIV-1 infected subjects 2 to 18 years of age received fosamprenavir with ritonavir with background nucleoside reverse transcriptase inhibitor therapy. 79% of subjects received greater than 48 weeks of exposure.
Overall the safety profile in these 158 children and adolescents was similar to that observed in the adult population. Vomiting occurred more frequently amongst paediatric patients. Drug-related adverse reactions were more common in APV20003 (57%) where subjects received once daily fosamprenavir/ritonavir when compared to APV29005 (33%) where subjects received twice daily fosamprenavir/ritonavir.
No new safety concerns were identified from analyses of 48 week data from studies APV29005 or APV20002, in which 54 subjects 4 weeks to <2 years of age received twice daily fosamprenavir/ritonavir with background nucleoside reverse transcriptase inhibitor therapy and 5 subjects received only single doses of fosamprenavir with or without ritonavir.
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors.
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