Telzir Oral Suspension

1. Name Of The Medicinal Product

Telzir® 50 mg/ml oral suspension

2. Qualitative And Quantitative Composition

Each ml of oral suspension contains 50 mg fosamprenavir as fosamprenavir calcium (equivalent to approximately 43 mg amprenavir).

Excipients:

Methyl parahydroxybenzoate (E218) 1.5 mg/ml

Propyl parahydroxybenzoate (E216) 0.2 mg/ml

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Oral suspension.

The suspension is white to off-white in colour.

4. Clinical Particulars

4.1 Therapeutic 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 (see section 5.1).

4.2 Posology And Method Of Administration

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.

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 (see section 4.4).

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 (see section 5.2).

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 (see section 5.2). Therefore, no recommendations can be made in this patient population.

Renal impairment

No dose adjustment is considered necessary in patients with renal impairment (see section 5.2).

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, 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 (see section 5.2), 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.

4.3 Contraindications

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

Telzir must not be administered concurrently with medicinal products with narrow therapeutic windows that are substrates of cytochrome P450 3A4 (CYP3A4), e.g. alfuzosin, amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, pimozide, quinidine, terfenadine, oral midazolam (for caution on parenterally administered midazolam, see section 4.5), oral triazolam, sildenafil used for the treatment of pulmonary arterial hypertension (for use of sildenafil in patients with erectile dysfunction, see sections 4.4 and 4.5).

Concomitant use of Telzir with simvastatin or lovastatin is contraindicated because of increased plasma concentrations of lovastatin and simvastatin which can increase the risk of myopathy, including rhabdomyolysis (see section 4.5).

Telzir with ritonavir must not be co-administered with medicinal products with narrow therapeutic windows that are highly dependent on CYP2D6 metabolism e.g. flecainide and propafenone (see section 4.5).

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

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 (see section 4.5).

4.4 Special Warnings And Precautions For Use

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 (see section 4.2).

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.

Medicinal products – interactions

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

PDE5 inhibitors used for the treatment of erectile dysfunction: The use of Telzir concomitantly with PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) is not recommended (see section 4.5).

Co-administration of Telzir with low dose ritonavir and these medicinal products is expected to substantially increase their concentrations and may result in PDE5 inhibitor-associated adverse events such as hypotension, visual changes and priapism (see section 4.5). Note that co-administration of Telzir with low dose ritonavir with sildenafil used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).

A reduction in the rifabutin dosage by at least 75 % is recommended when administered with Telzir with ritonavir. Further dose reduction may be necessary (see section 4.5).

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 (see section 4.5).

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 (see section 4.5).

Therapeutic concentration monitoring is recommended for immunosuppressant medicinal products (cyclosporine, tacrolimus, rapamycin) when co-administered with Telzir (see section 4.5).

Therapeutic concentration monitoring is recommended for tricyclic antidepressants (e.g. desipramine and nortriptyline) when co-administered with Telzir (see section 4.5).

When warfarin or other oral anticoagulants are co-administered with Telzir a reinforced monitoring of INR (International normalised ratio) is recommended (see section 4.5).

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 (see section 4.5).

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 life-threatening skin reactions, including Stevens-Johnson 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 (see section 4.8).

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.

Blood glucose testing should be performed prior to initiating therapy with Telzir and at periodic intervals during therapy.

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.

Lipid elevations

Treatment with fosamprenavir has resulted in increases in the concentration of triglycerides and cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating therapy with Telzir and at periodic intervals during therapy (see section 4.8).

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 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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 Amprenavir: AUC Amprenavir: Cmin Lopinavir: Cmax↔* Lopinavir: AUC ↔* Lopinavir: Cmin↔* * compared to lopinavir / ritonavir 400 mg/100 mg twice daily Amprenavir: Cmax Amprenavir: AUC Amprenavir: Cmin * 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 Atazanavir: AUC 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 AUC Cmin Raltegravir: Cmax AUC Cmin Fed state Amprenavir: Cmax AUC Cmin Raltegravir: Cmax AUC Cmin	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 (see section 4.3). 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 (see section 4.3). 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 (see section 4.3). 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 (see section 4.3). Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
NEUROLEPTIC
Pimozide	Pimozide: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Contraindicated (see section 4.3). 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 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 (see section 4.4).
Rifampicin 600mg once daily (Amprenavir without ritonavir) No FPV/RTV drug interaction studies	Amprenavir: AUC Significant (CYP3A4 induction by rifampicin)	Contraindicated (see section 4.3.) 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 Amprenavir: AUC Amprenavir: Cmin (C12h) ↔ Amprenavir: Cmax Amprenavir: AUC 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 Phenytoin: AUC Phenytoin: Cmin (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:   (Modest CYP3A4 induction)	Use with caution (see section 4.4).
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 (see section 4.4).
Halofantrine No drug interaction studies.	Halofantrine: ↑ expected (CYP3A4 inhibition by FPV/RTV)	Concomitant use is not recommended. It may cause serious adverse reactions (see section 4.4).
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 (see section 4.4). Note that co-administration of Telzir with low dose ritonavir with sildenafil used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).
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: 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 (see section 4.4). 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 (see section 4.4).