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Drug Details

TELZIR 50 mg/ml oral suspension (HIV)

• Drug Class Description
  Antiviral/Protease Inhibitor
• Generic Name
  Fosamprenavir
• Presentation
  Oral suspension. The suspension is white to off-white in colour
• Description
  Each ml of oral suspension contains 50 mg fosamprenavir as fosamprenavir calcium (equivalent to approximately 43 mg amprenavir).
• Indications
  Telzir in combination with low dose ritonavir is indicated for the treatment of Human Immunodeficiency Virus Type 1 (HIV-1) infected adults, adolescents and children of 6 years and above in combination with other antiretroviral medicinal products. In moderately antiretroviral experienced adults, Telzir in combination with low dose ritonavir has not been shown to be as effective as lopinavir / ritonavir. No comparative studies have been undertaken in children or adolescents. In heavily pretreated patients the use of Telzir in combination with low dose ritonavir has not been sufficiently studied. In protease inhibitor (PI) experienced patients, the choice of Telzir should be based on individual viral resistance testing and treatment history
• Adult Dosage
  

  Telzir must only be given with low dose ritonavir as a pharmacokinetic enhancer of amprenavir 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 Telzir.

  Therapy should be initiated by a physician experienced in the management of HIV infection.

  Telzir (fosamprenavir) is a pro-drug of amprenavir and must not be administered concomitantly with other medicinal products containing amprenavir.

  The importance of complying with the full recommended dosing regimen should be stressed to all patients.

  Caution is advised if the recommended dose of fosamprenavir with ritonavir detailed below are exceeded.

  Telzir suspension is administered orally.

  Shake the bottle vigorously for 20 seconds before first dose is removed and 5 seconds before each subsequent dose.

  Telzir is also available as 700 mg film-coated tablets.

  Adults

  In adults, the oral suspension should be taken without food and on an empty stomach.

  Please refer to the table below for the dosing recommendations in adults.

  Paediatric patients (from 6 years of age)

  In paediatric patients, the oral suspension should be taken with food in order to aid palatability and assist compliance.

  Telzir oral suspension is the recommended option for the most accurate dosing in children based on body weight.

  Please refer to the table below for the dosing recommendations in paediatric patients.

  No dosing recommendations can be made for children weighing less than 25 kg.

  Children less than 6 years of age: Telzir with ritonavir is not recommended in children below 6 years due to insufficient data on pharmacokinetics, safety and antiviral response (see section 5.2).

  Dosing recommendations for Telzir with ritonavir

  Age	Body weight	Telzir dose (TWICE DAILY)	Ritonavir dose (TWICE DAILY)
  Adult(> 18 years)		Tablet or Oral suspension 700 mg (1 tablet or 14 ml suspension) Oral suspension should be taken without food	Capsule or Solution 100 mg
  6-17 years	> 39 kg	Tablet or Oral suspension 700 mg (1 tablet or 14 ml suspension) Oral suspension should be taken with food	Capsule or Solution 100 mg
  	33-38 kg	Oral suspension 18 mg/kg (0.36 ml/kg ); maximum 700 mg or 14 ml Oral suspension should be taken with food	Capsule or Solution< 100 mg
  	25-32 kg	Oral suspension 18 mg/kg (0.36 ml/kg ) Oral suspension should be taken with food	Solution 3 mg/kg
  	<25 kg	No dosing recommendations
  <6 years		Not recommended

   

  Elderly (over 65 years of age)

  The pharmacokinetics of fosamprenavir have not been studied in this patient population.

  Renal impairment

  No initial dose adjustment is considered necessary in patients with renal impairment.

  Hepatic impairment

  For adults with mild hepatic impairment (Child-Pugh score: 5-6) the recommended dose is 700 mg fosamprenavir twice daily with 100 mg ritonavir once daily.

  For adults with moderate hepatic impairment (Child-Pugh score: 7-9) the recommended dose is 450 mg fosamprenavir (i.e. 9 ml Telzir oral suspension) twice daily with 100 mg ritonavir once daily.

  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.

  Even with these dose adjustments for adults with , some patients with hepatic impairment 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 a close monitoring of safety and virologic response is warranted.

  In this patient population, the oral suspension should be taken without food and on an empty stomach.

  No dose recommendation can be made for children and adolescents with hepatic impairment as no studies have been conducted in these age groups.

• Child Dosage
  Children (less than 12 years of age) and adolescents (12 to 17 years of age) The safety and efficacy of Telzir with ritonavir has not yet been established in these patient populations. Therefore, this combination must not be used in this age group until further data becomes available.
• Elderly Dosage
  The pharmacokinetics of fosamprenavir have not been studied in this patient population
• Contra Indications
  

  Hypersensitivity to fosamprenavir, amprenavir or to any of the excipients of Telzir, or to ritonavir.

  Telzir must not be administered concurrently with medicinal products with narrow therapeutic windows that are substrates of cytochrome P450 3A4 (CYP3A4), e.g. amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, pimozide, quinidine, terfenadine, oral midazolam , oral triazolam.

  Telzir with ritonavir must not be coadministered with medicinal products with narrow therapeutic windows that are highly dependent on CYP2D6 metabolism e.g. flecainide and propafenone.

  Combination of rifampicin with Telzir with concomitant low-dose ritonavir is contraindicated.

  Herbal preparations containing St John's wort (Hypericum perforatum) must not be used while taking Telzir due to the risk of decreased plasma concentrations and reduced clinical effects of amprenavir.

• Special Precautions
  

  Patients should be advised that treatment with the Telzir, or any other current antiretroviral therapy, does not cure HIV and that they may still develop opportunistic infections and other complications of HIV infection. Current antiretroviral therapies, including Telzir, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

  Fosamprenavir contains a sulphonamide moiety. The potential for cross-sensitivity between medicinal products in the sulphonamide class and fosamprenavir is unknown. In the pivotal studies of Telzir, in patients receiving fosamprenavir with ritonavir there was no evidence of an increased risk of rashes in patients with a history of sulphonamide allergy versus those who did not have a sulphonamide allergy. Yet, Telzir should be used with caution in patients with a known sulphonamide allergy.

  The Telzir oral suspension contains propyl and methyl parahydroxybenzoate. These products may cause an allergic reaction in some individuals. This reaction may be delayed.

  Co-administration of Telzir 700 mg twice daily with ritonavir in doses greater than 100 mg twice daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of the combination and therefore is not recommended.

  Liver disease

  Telzir with ritonavir should be used with caution and at reduced doses in adults with mild, moderate or severe hepatic impairment.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 events. 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.

  Medicinal products – interactions

  The use of Telzir concomitantly with halofantrine or lidocaine (systemic) is not recommended.

  The use of Telzir concomitantly with PDE5 inhibitors (e.g. sildenafil and vardenafil) is not recommended.

  Concomitant use of Telzir with simvastatin or lovastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis.

  A reduction in the rifabutin dosage by at least 75 % is recommended when administered with Telzir with ritonavir. Further dose reduction may be necessary.

  Because there may be an increased risk of hepatic transaminase elevations and hormonal levels may be altered with co-administration of fosamprenavir, ritonavir and oral contraceptives, alternative non-hormonal methods of contraception are recommended for women of childbearing potential.

  No data are available on the co-administration of fosamprenavir and ritonavir with oestrogens and/or progestogens when used as hormonal replacement therapies. The efficacy and safety of these therapies with fosamprenavir and ritonavir has not been established.

  Anticonvulsants (carbamazepine, phenobarbital) should be used with caution. Telzir may be less effective due to decreased amprenavir plasma concentrations in patients taking these medicinal products concomitantly.

  Therapeutic concentration monitoring is recommended for immunosuppressant medicinal products (cyclosporine, tacrolimus, rapamycin) when co-administered with Telzir.

  Therapeutic concentration monitoring is recommended for tricyclic antidepressants (e.g. desipramine and nortriptyline) when co-administered with Telzir .

  When warfarin or other oral anticoagulants are co-administered with Telzir a reinforced monitoring of INR (International normalised ratio) is recommended.

  Concomitant use of Telzir with 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.

  Rash / cutaneous reactions

  Most patients with mild or moderate rash can continue Telzir. Appropriate antihistamines (e.g. cetirizine dihydrochloride) may reduce pruritus and hasten the resolution of rash. Severe and lifethreatening skin reactions, including StevensJohnson syndrome, were reported in less than 1 % of patients included in the clinical development programme. Telzir should be permanently discontinued in case of severe rash, or in case of rash of moderate intensity with systemic or mucosal symptoms.

  Haemophiliac patients

  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.

  Hyperglycaemia

  New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus have been reported in patients receiving antiretroviral therapy, including protease inhibitors. In some of these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many of the patients had confounding medical conditions, some of which required therapy with medicinal products that have been associated with the development of diabetes mellitus or hyperglycaemia.

  Lipodystrophy

  Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. 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 mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

  Osteonecrosis:

  Although the etiology 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
  

  When fosamprenavir and ritonavir are co-administered, the ritonavir metabolic drug interaction profile may predominate because ritonavir is a more potent CYP3A4 inhibitor. The full prescribing information for ritonavir must therefore be consulted prior to initiation of therapy with Telzir with ritonavir. Ritonavir also inhibits CYP2D6 but to a lesser extent than CYP3A4. Ritonavir induces CYP3A4, CYP1A2, CYP2C9 and glucuronosyl transferase. Additionally, both amprenavir, the active metabolite of fosamprenavir, and ritonavir are primarily metabolised in the liver by CYP3A4. Therefore, any medicinal products that either share this metabolic pathway or modify CYP3A4 activity may modify the pharmacokinetics of amprenavir and ritonavir. Similarily, administration of fosamprenavir with ritonavir may modify the pharmacokinetics of other active substances that share this metabolic pathway.

  Interaction studies have only been performed in adults.

  Unless otherwise stated, studies detailed below have been performed with the recommended dosage of fosamprenavir/ritonavir (i.e. 700/100 mg twice daily), and the interaction was assessed under steady-state conditions where drugs were administered for 10 to 21 days,

   

  Drugs by Therapeutic Area	Interaction Geometric mean change (%) (Possible mechanism)	Recommendation concerning co-administration
  ANTIRETROVIRAL MEDICINAL PRODUCTS Non-nucleoside reverse transcriptase inhibitors:
  Efavirenz 600 mg once daily	No clinically significant interaction is observed.	No dosage adjustment necessary.
  Nevirapine 200mg twice daily	No clinically significant interaction is observed.	No dosage adjustment necessary.
  Etravirine (Study conducted in 8 patients)	Amprenavir AUC ↑ 69% Amprenavir Cmin↑ 77% Amprenavir Cmax↑ 62% Etravirine AUC ↔a Etravirine Cmin↔a Etravirine Cmax↔a a Comparison based on historic control.	Telzir may require dose reduction (using oral suspension)
  Nucleoside / Nucleotide reverse transcriptase inhibitors:
  Abacavir Lamivudine Zidovudine Study performed with amprenavir. No FPV/RTV drug interaction studies.	No clinically significant interaction is expected.	No dosage adjustment necessary.
  Didanosine chewable tablet No drug interaction studies.	No clinically significant interaction is expected.	No dose separation or dosage adjustment necessary (see Antacids).
  Didanosine gastro-resistant capsule No drug interaction studies.	No clinically significant interaction is expected.	No dosage adjustment necessary.
  Tenofovir 300mg once daily	No clinically significant interaction observed.	No dosage adjustment necessary.

   

  Protease Inhibitors: According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.
  Lopinavir / ritonavir 400 mg/100 mg twice daily                     Lopinavir / ritonavir 533 mg/133 mg twice daily (Telzir 1400 mg twice daily)	Lopinavir: Cmax↑ 30% Lopinavir: AUC ↑ 37% Lopinavir: Cmin ↑ 52% Amprenavir: Cmax 58% Amprenavir: AUC  63% Amprenavir: Cmin 65% Lopinavir: Cmax↔* Lopinavir: AUC ↔* Lopinavir: Cmin↔* * compared to lopinavir / ritonavir 400 mg/100 mg twice daily Amprenavir: Cmax 13%* Amprenavir: AUC  26%* Amprenavir: Cmin 42 %* * compared to fosamprenavir / ritonavir 700 mg/100 mg twice daily (Mixed CYP3A4 induction/inhibition, Pgp induction)	Concomitant use is not recommended.
  Indinavir Saquinavir Nelfinavir No drug interaction studies.		No dose recommendations can be given.
  Atazanavir 300 mg once daily	Atazanavir: Cmax  24%* Atazanavir: AUC 22%* Atazanavir: Cmin↔* *compared to atazanavir/ ritonavir 300 mg/ 100 mg once daily Amprenavir: Cmax↔ Amprenavir: AUC ↔ Amprenavir: Cmin↔	No dosage adjustment necessary.
  Integrase inhibitors
  Raltegravir 400 mg twice daily	Fasting state Amprenavir: Cmax  14% (-36%; +15%) AUC  16% (-36%; +8%) Cmin  19% (-42%; +13%) Raltegravir: Cmax  51% (-75%; -3%) AUC  55% (-76%; -16%) Cmin  36 % (-57%; -3%) Fed state Amprenavir: Cmax 25% (-41%; -4%) AUC 25% (-42%; -3%) Cmin  33% (-50%; -10%)   Raltegravir: Cmax 56% (-70%; -34%) AUC 54% (-66%; -37%) Cmin  54 % (-74%; -18%)	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.

   

  ANTIARRHYTHMICS
  Amiodarone Bepridil Quinidine Flecainide Propafenone	Amiodarone: ↑ expected Bepridil: ↑ expected Quinidine: ↑ expected (CYP3A4 inhibition by FPV/RTV) Flecainide: ↑ expected Propafenone: ↑ expected (CYP2D6 inhibition by RTV)	Contraindicated. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  ERGOT DERIVATIVES
  Dihydroergotamine Ergotamine Ergonovine Methylergonovine	Dihydroergotamine: ↑ expected Ergonovine: ↑ expected Ergotamine: ↑ expected Methylergonovine: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Contraindicated. Potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
  GASTROINTESTINAL MOTILITY AGENTS
  Cisapride	Cisapride: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Contraindicated. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  ANTIHISTAMINES (HISTAMINE H1 RECEPTOR ANTAGONISTS)
  Astemizole Terfenadine	Astemizole: ↑ expected Terfenadine: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Contraindicated. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  NEUROLEPTIC
  Pimozide	Pimozide: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Contraindicated. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

   

  INFECTION
  Antibacterials:
  Clarithromycin Study performed with amprenavir. No FPV/RTV drug interaction studies.	Clarithromycin: moderate ↑ expected (CYP3A4 inhibition)	Use with caution
  Erythromycin No drug interaction studies.	Erythromycin: ↑ expected (CYP3A4 inhibition by FPV/RTV	Use with caution.
  Anti-mycobacterial:
  Rifabutin 150 mg every other day	Rifabutin: Cmax  14%* Rifabutin: AUC(0-48) ↔* 25-O-desacetylrifabutin: Cmax↑ 6-fold* 25-O-desacetylrifabutin: AUC(0-48) ↑ 11-fold* *compared to rifabutin 300 mg once daily Amprenavir exposure unchanged when compared to historical data. (Mixed CYP3A4 induction/inhibition)	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.
  Rifampicin 600mg once daily (Amprenavir without ritonavir) No FPV/RTV drug interaction studies	Amprenavir: AUC  82% Significant  APV expected (CYP3A4 induction by rifampicin)	Contraindicated  The decrease in amprenavir AUC can result in virological failure and resistance development. During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with ritonavir, a high frequency of liver reactions was seen.

   

  Anti-fungals:
  Ketoconazole 200 mg once daily for four days       Itraconazole No drug interaction studies.	Ketoconazole: Cmax↑ 25% Ketoconazole: AUC ↑ 2.69-fold. Amprenavir: Cmax ↔ Amprenavir: AUC ↔ Amprenavir: Cmin ↔ Itraconazole: ↑ expected (CYP3A4 inhibition by FPV/RTV)	High doses (> 200 mg/day) of ketoconazole or itraconazole are not recommended.
  ANTACIDS, HISTAMINE H2 RECEPTOR ANTAGONIST AND PROTON-PUMP INHIBITORS
  Single 30 ml dose of antacid suspension (equivalent to 3.6 grams aluminium hydroxide and 1.8 grams magnesium hydroxide (Telzir 1400 mg single dose) Ranitidine 300 mg single dose (Telzir 1400 mg single dose) Esomeprazole 20 mg once daily	Amprenavir: Cmax 35% Amprenavir: AUC  18% Amprenavir: Cmin (C12h) ↔ Amprenavir: Cmax 51% Amprenavir: AUC  30% Amprenavir: Cmin (C12h) ↔ Amprenavir Cmax ↔ Amprenavir AUC ↔ Amprenavir Cmin (C12h) ↔ (Increase in gastric pH)	No dosage adjustment necessary with antacids, proton-pump inhibitors or histamine H2 receptor antagonists.
  ANTICONVULSANTS
  Phenytoin 300 mg once daily	Phenytoin: Cmax 20% Phenytoin: AUC  22% Phenytoin: Cmin 29% (Modest induction of CYP3A4 by FPV/RTV) Amprenavir: Cmax ↔ Amprenavir: AUC ↑ 20% Amprenavir: Cmin ↑ 19%	It is recommended that phenytoin plasma concentrations be monitored and phenytoin dose increased as appropriate.

   

  Phenobarbital Carbamazepine No drug interaction studies.	Amprenavir:  expected   (Modest CYP3A4 induction)	Use with caution.
  Lidocaine (by systemic route) No drug interaction studies.	Lidocaine: ↑ expected   (CYP3A4 inhibition by FPV/RTV)	Concomitant use is not recommended. It may cause serious adverse reactions.
  Halofantrine No drug interaction studies.	Halofantrine: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Concomitant use is not recommended. It may cause serious adverse reactions.
  PDE5 INHIBITORS
  Sildenafil Vardenafil Tadalafil No drug interaction studies.	PDE5 inhibitors: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Concomitant use is not recommended. It may result in an increase in PDE5 inhibitor associated adverse reactions, including hypotension, visual changes and priapism (refer to PDE5 inhibitor prescribing information). Patients should be warned about these possible side effects when using PDE5 inhibitors with Telzir/ritonavir. Note that co-administration of Telzir with low dose ritonavir with sildenafil used for the treatment of pulmonary arterial hypertension is contraindicated.
  INHALED/NASAL STEROIDS
  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)	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.
  ALPHA 1-ADRENORECEPTOR ANTAGONIST
  Alfuzosin,	Potential for increased alfuzosin concentrations which can result in hypotension. The mechanism of interaction is CYP3A4 inhibition by fosamprenavir/ritonavir.	Co-administration of TELZIR/ritonavir with alfuzosin is contraindicated

   

  HERBAL PRODUCTS
  St. John's wort (Hypericum perforatum)	Amprenavir  expected (CYP3A4 induction by St. John's wort)	Herbal preparations containing St John's wort must not be combined with Telzir. If a patient is already taking St John's wort, check amprenavir, ritonavir and HIV RNA and stop St John's wort. Amprenavir and ritonavir levels may increase on stopping St John's wort. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort.
  HMG-COA REDUCTASE INHIBITORS
  Lovastatin Simvastatin No drug interaction studies.	Lovastatin: ↑ expected Simvastatin: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Concomitant use is not recommended. Increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis. Pravastatin or fluvastatin are recommended because their metabolism is not dependent on CYP 3A4 and interactions are not expected with protease inhibitors.
  Atorvastatin 10 mg once daily for 4 days	Atorvastatin: Cmax ↑ 184% Atorvastatin: AUC ↑ 153% Atorvastatin: Cmin ↑ 73% Amprenavir: Cmax ↔ Amprenavir: AUC ↔ Amprenavir: Cmin ↔ (CYP3A4 inhibition by FPV/RTV)	Doses of atorvastatin no greater than 20 mg/day should be administered, with careful monitoring for atorvastatin toxicity.
  IMMUNOSUPPRESSANTS
  Cyclosporin Rapamycin Tacrolimus No drug interaction studies.	Cyclosporin: ↑ expected Rapamycin: ↑ expected Tacrolimus: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Frequent therapeutic concentration monitoring of immunosuppressant levels is recommended until levels have stabilised.

   

  BENZODIAZEPINES
  Midazolam 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)	Telzir/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 Telzir/ritonavir is co-administered 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.
  TRICYCLIC ANTIDEPRESSANTS
  Desipramine Nortriptyline No drug interaction studies.	Tricyclic antidepressant: ↑ expected   (Mild CYP2D6 inhibition by RTV)	Careful monitoring of the therapeutic and adverse reactions of tricyclic antidepressants is recommended.
  OPIOIDS
  Methadone  200 mg once daily	(R-) methadone: Cmax 21% (R-) methadone: AUC  18% (CYP induction by FPV/RTV)	The decrease of (R-) methadone (active enantiomer) is not expected to be clinically significant. As a precaution, patients should be monitored for withdrawal syndrome.
  ORAL ANTICOAGULANTS
  Warfarin Other oral anticoagulants No drug interaction studies.	Possible  or ↑ of antithrombotic effect.   (Induction and/or inhibition of CYP2C9 by RTV)	Reinforced monitoring of the International Normalised Ratio is recommended.

   

  ORAL CONTRACEPTIVES
  Ethinyl estradiol 0.035 mg/norethisterone 0.5 mg once daily	Ethinyl estradiol: Cmax28% Ethinyl estradiol: AUC 37% Norethisterone: Cmax38% Norethisterone: AUC 34% Norethisterone: Cmin 26 (CYP3A4 induction by FPV/RTV) Amprenavir: Cmax ↔* Amprenavir: AUC ↔* Amprenavir: Cmin ↔* * compared to historical data Ritonavir: Cmax ↑63%* Ritonavir: AUC ↑45%* * compared to historical data Clinically significant hepatic transaminase elevations occurred in some subjects.	Alternative non-hormonal methods of contraception are recommended for women of childbearing potential.
  SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)
  Paroxetine 20 mg once daily	Paroxetine: Cmax  51% Paroxetine: AUC 55% Amprenavir: Cmax ↔* Amprenavir: AUC ↔* Amprenavir: Cmin ↔* * compared to historical data Mechanism unknown.	Dose titration of paroxetine based on a clinical assessment of antidepressant response is recommended. Patients on stable dose of paroxetine who start treatment with Telzir and ritonavir should be monitored for antidepressant response.

• Adverse Drug Reactions
  

  It should be noted that the Telzir oral suspension has not been evaluated clinically in adults and that the adverse reaction profile detailed in this section is based on the experience in adults with the Telzir film coated tablets.

  The safety of fosamprenavir has been studied in 755 adult patients in Phase II and III controlled clinical trials. The safety of the co-administration of fosamprenavir with low dose ritonavir was established in two pivotal Phase III trials: APV30002 (n = 322) in antiretroviral naïve patients, fosamprenavir (1400 mg) given once daily in combination with ritonavir (200 mg) as part of a triple regimen including abacavir and lamivudine. APV30003 in protease inhibitor experienced patients, fosamprenavir given in combination with low dose ritonavir either once daily (1400 mg / 200 mg) (n = 106) or twice daily (700 mg / 100 mg) (n = 106) in combination with two active reverse transcriptase inhibitors (RTIs).

  The adverse reaction profile was similar across all the respective adult studies: antiretroviral naïve (APV30002) and protease inhibitor experienced (twice daily dosing, APV30003) patient populations.

  Adverse reactions are listed by MedDRA system organ class and absolute frequency. Frequencies.are defined as: Very common ( 1/10), Common ( 1/100, < 1/10), Uncommon ( 1/1,000, < 1/100), Rare ( 1/10,000, < 1/1,000) or Very rare (< 1/10,000), including isolated reports.

  Frequency categories for the events below have been based on clinical trials and postmarketing data.

  Most of the adverse events below were reported from two 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.

  Body System	Adverse reaction	Frequency
  Nervous system disorders	Headache, dizziness, oral paraesthesia	Common
  Gastrointestinal disorders	Diarrhoea	Very common
  	Loose stools, nausea, vomiting, abdominal pain	Common
  Skin and subcutaneous tissue disorders	Rash (see text below “rash/cutaneous reactions”)	Common
  	Angioedema	Uncommon
  	Stevens Johnson syndrome	Rare
  General disorders and administration site conditions	Fatigue	Common

  Children and adolescents: The adverse event profile in children and adolescents is based on integrated safety data from two studies (APV29005 and APV20003) in which 126 HIV-1 infected subjects 2 to 18 years of age received fosamprenavir with ritonavir with background nucleoside reverse transcriptase inhibitor therapy. 70 % of subjects received greater than 48 weeks of exposure.

  Overall the safety profile in these 126 children and adolescents was similar to that observed in the adult population. Drug-related adverse events were more common in APV20003 (55%) where subjects received once daily fosamprenavir / ritonavir when compared to APV29005 (39%) where subjects received twice daily fosamprenavir / ritonavir.

  Rash / cutaneous reactions: 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 lifethreatening 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: 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 (very common). Grade 3 or 4 elevations in total cholesterol values were observed in less than 1 % of adult patients (< 1 % APV30002 ; 0 % APV 30003).

  Lipodystrophy: combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

  Metabolic abnormalities: combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.

  Hyperglycaemia: new onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus have been reported in patients receiving antiretroviral protease inhibitors.

  Rhabdomyolysis: an increase in CPK, myalgia, myositis, and rarely, rhabdomyolysis, have been reported with protease inhibitors, more specifically in association with nucleoside analogues.

  Haemophiliac patients: there have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors.

  Immune Reactivation Syndrome: 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.

  Osteonecrosis: 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.