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Prezista(Darunavir tabs)

2015-06-03 09:48:43 来源: 作者: 【大中小】浏览:322次评论:0条

INDICATIONS & USAGE

PREZISTA is a human immunodeficiency virus (HIV-1) protease inhibitor indicated for the treatment of HIV-1 infection in adult patients. PREZISTA is also indicated for the treatment of HIV-1 infection in pediatric patients 3 years of age and older. PREZISTA must be co-administered with ritonavir (PREZISTA/ritonavir) and with other antiretroviral agents. (1)

PREZISTA®, co-administered with ritonavir (PREZISTA/ritonavir), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection.

This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from 2 controlled Phase 3 trials of 48 weeks duration in antiretroviral treatment-naïve and treatment-experienced patients and 2 controlled Phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients.

PREZISTA, co-administered with ritonavir (PREZISTA/ritonavir), and with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in pediatric patients 3 years of age and older [see Use in Specific Populations (8.4)].

The indication for treatment-experienced pediatric patients 3 to less than 18 years of age is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from two open-label Phase 2 trials in antiretroviral treatment-experienced pediatric subjects(24-week analysis for one trial in patients 6 to less than 18 years of age; 48-week analysis for one trial in patients 3 to less than 6 years of age) . The indication for treatment-naïve pediatric patients or antiretroviral treatment-experienced patients with no darunavir resistance associated substitutions is based on one open-label Phase 2 trial of 48 weeks duration in antiretroviral treatment-naïve subjects 12 to less than 18 years of age and pharmacokinetic modeling and simulation for patients 3 to less than 12 years of age.

In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with PREZISTA/ritonavir:

Treatment history and, when available, genotypic or phenotypic testing should guide the use of PREZISTA/ritonavir [see Clinical Pharmacology (12.4)].
The use of other active agents with PREZISTA/ritonavir is associated with a greater likelihood of treatment response [see Clinical Pharmacology (12.4) and Clinical Studies (14.3)].

DOSAGE & ADMINISTRATION

Treatment-naïve adult patients and treatment-experienced adult patients with no darunavir resistance associated substitutions: 800 mg (one 800 mg tablet or two 400 mg tablets) taken with ritonavir 100 mg once daily and with food. (2.1)
Treatment-experienced adult patients with at least one darunavir resistance associated substitution: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food. (2.1)
Pediatric patients (3 to less than 18 years of age and weighing at least 10 kg): dosage of PREZISTA and ritonavir is based on body weight and should not exceed the adult dose. PREZISTA should be taken with ritonavir and with food. (2.2)
PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment. (2.3)

PREZISTA must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer PREZISTA with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.

Patients who have difficulty swallowing PREZISTA tablets can use the 100 mg/mL PREZISTA oral suspension.

Treatment-Naïve Adult Patients

The recommended oral dose of PREZISTA is 800 mg (one 800 mg tablet or two 400 mg tablets or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL of a 80 mg/mL ritonavir oral solution) once daily and with food. An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe.

Treatment-Experienced Adult Patients

Table 1: Treatment-Experienced Adult Patients
With no darunavir resistance associated substitutions*	With at least one darunavir resistance associated substitution1
Formulations: PREZISTA tablets or oral suspension (100 mg/mL) and ritonavir tablets/capsules (100 mg) or solution (80 mg/mL)
PREZISTA 800 mg (one 800 mg tablet or two 400 mg tablets) or 8 mL†(oral suspension) once daily with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL (oral solution) once daily and with food	PREZISTA 600 mg (e.g. one 600 mg tablet) or 6 mL (oral suspension) twice daily with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL (oral solution) twice daily and with food

For antiretroviral treatment-experienced patients genotypic testing is recommended. However, when genotypic testing is not feasible, PREZISTA/ritonavir 600/100 mg twice daily dosing is recommended.

Healthcare professionals should pay special attention to accurate dose selection of PREZISTA, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose.

Prescribers should select the appropriate dose of PREZISTA/ritonavir for each individual child based on body weight (kg) and should not exceed the recommended dose for adults.

Before prescribing PREZISTA, children weighing greater than or equal to 15 kg should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of PREZISTA oral suspension should be considered.

The recommended dose of PREZISTA/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight (see Tables 2, 3, 4, and 5) and should not exceed the recommended adult dose. PREZISTA should be taken with ritonavir and with food.

The recommendations for the PREZISTA/ritonavir dosage regimens were based on the following:

Twice daily dosing

Results from two trials in treatment-experienced pediatric subjects 3 to less 18 years of age demonstrating similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-experienced adults.

Once daily dosing

Results from one trial in treatment-naive pediatric subjects 12 to less than 18 years of age demonstrating similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-naive adults.
Results from population pharmacokinetic modeling and simulation in children 3 to less than 12 years of age predicting similar darunavir plasma exposures compared to treatment-naïve adults. Although no clinical trial was conducted to collect exposure-safety data, the predicted exposures from the once daily dosing is supported by exposures observed in a pediatric clinical trial where twice-daily dosing was administered.

Dosing recommendations for treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions

• Pediatric patients weighing at least 10 kg but less than 15 kg

The weight-based dose in antiretroviral treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions is PREZISTA 35 mg/kg once daily with ritonavir 7 mg/kg once daily using the following table.

Table 2: Recommended dose for pediatric patients weighing 10 kg to less than 15 kg who are treatment-naïve or treatment-experienced with no darunavir resistance associated substitutions*
Body weight (kg)	Formulation: PREZISTA oral suspension (100 mg/mL) and Ritonavir oral solution (80 mg/mL)
	Dose: once daily with food
Greater than or equal to 10 kg to less than 11 kg	PREZISTA 3.6 mL† (350 mg) with ritonavir 0.8 mL (64 mg)
Greater than or equal to 11 kg to less than 12 kg	PREZISTA 4 mL4 (385 mg) with ritonavir 0.8 mL (64 mg)
Greater than or equal to 12 kg to less than 13 kg	PREZISTA 4.2 mL (420 mg) with ritonavir 1 mL (80 mg)
Greater than or equal to 13 kg to less than 14 kg	PREZISTA 4.6 mL4 (455 mg) with ritonavir 1 mL (80 mg)
Greater than or equal to 14 kg to less than 15 kg	PREZISTA 5 mL4 (490 mg) with ritonavir 1.2 mL (96 mg)

4
Pediatric patients weighing at least 15 kg

Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or solution using the following table:

Table 3: Recommended dose for pediatric patients weighing at least 15 kg who are treatment-naïve or treatment-experienced with no darunavir resistance associated substitions*
Body Weight (kg)	Formulation: PREZISTA tablet(s) and ritonavir capsules or tablets (100 mg)	Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL)
	Dose: once daily with food	Dose: once daily with food
Greater than or equal to 15 kg to less than 30 kg	PREZISTA 600 mg with ritonavir 100 mg	PREZISTA 6 mL (600 mg) with ritonavir 1.25 mL (100 mg)
Greater than or equal to 30 kg to less than 40 kg	PREZISTA 675 mg with ritonavir 100 mg	PREZISTA 6.8 mL†‡ (675 mg) with ritonavir 1.25 mL (100 mg)
Greater than or equal to 40 kg	PREZISTA 800 mg with ritonavir 100 mg	PREZISTA 8 mL7 (800 mg) with ritonavir 1.25 mL (100 mg)

Dosing recommendations for treatment-experienced pediatric patients with at least one darunavir resistance associated substitutions

• Pediatric patients weighing at least 10 kg but less than 15 kg

The weight-based dose in antiretroviral treatment-experienced pediatric patients with at least one darunavir resistance associated substitution is PREZISTA 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily using the following table:

Table 4: Recommended dose for pediatric patients weighing 10 kg to less than 15 kg who are treatment-experienced with at least one darunavir resistance associated substitution*
Body weight (kg)	Formulation: PREZISTA oral suspension (100 mg/mL) and Ritonavir oral solution (80 mg/mL)
	Dose: twice daily with food
Greater than or equal to 10 kg to less than 11 kg	PREZISTA 2 mL (200 mg) with ritonavir 0.4 mL (32 mg)
Greater than or equal to 11 kg to less than 12 kg	PREZISTA 2.2 mL (220 mg) with ritonavir 0.4 mL (32 mg)
Greater than or equal to 12 kg to less than 13 kg	PREZISTA 2.4 mL (240 mg) with ritonavir 0.5 mL (40 mg)
Greater than or equal to 13 kg to less than 14 kg	PREZISTA 2.6 mL (260 mg) with ritonavir 0.5 mL (40 mg)
Greater than or equal to 14 kg to less than 15 kg	PREZISTA 2.8 mL (280 mg) with ritonavir 0.6 mL (48 mg)

• Pediatric patients weighing at least 15 kg

Pediatric patients weighing at least 15 kg can be dosed with PREZISTA oral tablet(s) or solution using the following table:

Table 5: Recommended dose for pediatric patients weighing at least 15 kg who are treatment-experienced with at least one darunavir resistance associated substitution*
Body Weight (kg)	Formulation: PREZISTA tablet(s) and ritonavir tablets, capsules (100 mg) or oral solution (80 mg/mL)	Formulation: PREZISTA oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL)
	Dose: twice daily with food	Dose: twice daily with food
Greater than or equal to 15 kg to less than 30 kg	PREZISTA 375 mg with ritonavir 0.6 mL (48 mg)	PREZISTA 3.8 mL (375 mg) with ritonavir 0.6 mL (48 mg)
Greater than or equal to 30 kg to less than 40 kg	PREZISTA 450 mg with ritonavir 0.75 mL (60 mg)	PREZISTA 4.6 mL (450 mg)† with ritonavir 0.75 mL (60 mg)
Greater than or equal to 40 kg	PREZISTA 600 mg with ritonavir 100 mg	PREZISTA 6 mL (600 mg) with ritonavir 1.25 mL (100 mg)

Do not use PREZISTA/ritonavir in pediatric patients below 3 years of age [see Warnings and Precautions (5.11) and Nonclinical Toxicology (13.2)].

No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available regarding the use of PREZISTA/ritonavir when co-administered to subjects with severe hepatic impairment; therefore, PREZISTA/ritonavir is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

1: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V
2: An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe
3: darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
4: The 350 mg, 385 mg, 455 mg and 490 mg darunavir dose for the specified weight groups were rounded up for suspension dosing convenience to 3.6 mL, 4 mL, 4.6 mL and 5 mL, respectively.
5: darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
6: The 675 mg dose using darunavir tablets for this weight group is rounded up to 6.8 mL for suspension dosing convenience.
7: The 6.8 mL and 8 mL darunavir dose should be taken as two (3.4 mLor 4 mL respectively) administrations with the included oral dosing syringe
8: darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
9: darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
10: The 375 mg and 450 mg dose using darunavir tablets for this weight group is rounded up to 3.8 mL and 4.6 mL for suspension dosing convenience.