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Crixivan

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Clinical Pharmacology

Crixivan

Pregnant Patients: The optimal dosing regimen for use of indinavir in pregnant patients has not been established. A CRIXIVAN dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). The mean indinavir plasma AUC0-8hr at weeks 30-32 of gestation (n=11) was 9231 nM•hr, which is 74% (95% CI: 50%, 86%) lower than that observed 6 weeks postpartum. Six of these 11 (55%) patients had mean indinavir plasma concentrations 8 hours post-dose (Cmin) below assay threshold of reliable quantification. The pharmacokinetics of indinavir in these 11 patients at 6 weeks postpartum were generally similar to those observed in non-pregnant patients in another study (see PRECAUTIONS, Pregnancy).

Drug Interactions: (also see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: DRUG INTERACTIONS)

Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of CRIXIVAN and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects (see CONTRAINDICATIONS and WARNINGS). Based on in vitro data in human liver microsomes, indinavir does not inhibit CYP1A2, CYP2C9, CYP2E1 and CYP2B6. However, indinavir may be a weak inhibitor of CYP2D6.

Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of CRIXIVAN and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir.

Drug interaction studies were performed with CRIXIVAN and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of CRIXIVAN on the AUC, Cmax and Cmin are summarized in Table 2 (effect of other drugs on indinavir) and Table 3 (effect of indinavir on other drugs). For information regarding clinical recommendations, see Table 9 in PRECAUTIONS.

Table 2 Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)


Coadministered drug Dose of Coadministered
drug (mg)		 Dose of CRIXIVAN
(mg)		 n Ratio (with/without coadministered drug) of Indinavir
Pharmacokinetic Parameters
(90% CI); No Effect =1.00
        C AUC C
Cimetidine 600 twice daily, 6 days 400 single
dose		 12 1.07
(0.77, 1.49)		 0.98
(0.81, 1.19)		 0.82
(0.69, 0.99)
Clarithromycin 500 q12h, 7 days 800 three
times daily,
7 days		 10 1.08
(0.85, 1.38)		 1.19
(1.00, 1.42)		 1.57
(1.16, 2.12)
Delavirdine 400 three times daily 400 three times
daily, 7 days		 28 0.641
(0.48, 0.86)		 No significant
change1		 2.181
(1.16, 4.12)
Delavirdine 400 three times daily 600 three times
daily, 7 days		 28 No significant
change		 1.531
(1.07, 2.20)		 3.981
(2.04, 7.78)
Efavirenz2 600 once daily, 10
days		 1000 three times
daily, 10 days
After morning dose
After afternoon dose
After eveningdose		 20 No significant
change1
No significant
change1
0.711
(0.57, 0.89)		 0.671
(0.61, 0.74)
0.631
(0.54, 0.74)
0.541
(0.46, 0.63)		 0.611
(0.49, 0.76)
0.481
(0.43, 0.53)
0.431
(0.37, 0.50)
Fluconazole2 400 once daily, 8 days 1000 three times
daily, 7 days		 11 0.87
(0.72, 1.05)		 0.76
(0.59, 0.98)		 0.90
(0.72, 1.12)
Grapefruit Juice 8 oz. 400 single dose 10 0.65
(0.53, 0.79)		 0.73
(0.60, 0.87)		 0.90
(0.71, 1.15)
Isoniazid 300 once daily in the morning, 8 days 800 three times
daily, 7 days		 11 0.95
(0.88, 1.03)		 0.99
(0.87, 1.13)		 0.89
(0.75, 1.06)
Itraconazole 200 twice daily, 7 days 600 three times
daily, 7 days		 12 0.783
(0.69, 0.88)		 0.993
(0.91, 1.06)		 1.493
(1.28, 1.74)
Ketoconazole 400 once daily, 7 days 600 three times
daily, 7 days		 10 1.143
(0.93, 1.40)		 1.623
(1.38, 1.92)		 2.803
(2.20, 3.57)
Methadone 20-60 once daily in the
morning, 8 days		 800 three times
daily, 8 days		 10 See text below for discussion of interaction.
Quinidine 200 single dose 400 single dose 10 0.96
(0.79, 1.18)		 1.07
(0.89, 1.28)		 0.93
(0.73, 1.19)
Rifabutin 150 once daily inthe
morning, 10days		 800 three times
daily, 10 days		 14 0.80
(0.72, 0.89)		 0.68
(0.60, 0.76)		 0.60
(0.51, 0.72)
Rifabutin 300 once daily in the
morning, 10 days		 800 three times
daily, 10 days		 10 0.75
(0.61, 0.91)		 0.66
(0.56, 0.77)		 0.61
(0.50, 0.75)
Rifampin 600 once daily in the
morning,8 days		 800 three times
daily, 7 days		 12 0.13
(0.08, 0.22)		 0.08
(0.06, 0.11)		 Not Done
Ritonavir 100 twice daily, 14
days		 800 twice
daily, 14days		 10, 163 See text below for discussion of interaction.
Ritonavir 200 twice daily, 14 days 800 twice
daily, 14days		 9, 163 See text below for discussion of interaction.
Sildenafil 25 single dose 800 three
times daily		 6 See text below for discussion of interaction.
St. John's wort
(Hypericum perforatum,
standardized to 0.3 %hypericin)		 300 three times daily
with meals, 14 days		 800 three
times
daily		 8 Not Available 0.46
(0.34, 0.58)4		 0.19
(0.06, 0.33)4
Stavudine (d4T)2 40 twice daily, 7 days 800 three times
daily, 7 days		 11 0.95
(0.80, 1.11)		 0.95
(0.80, 1.12)		 1.13
(0.83, 1.53)
Trimethoprim/
Sulfamethoxazole		 800 Trimethoprim/
160 Sulfamethoxazole
q12h, 7 days		 400 four times
daily, 7 days		 12 1.12
(0.87, 1.46)		 0.98
(0.81, 1.18)		 0.83
(0.72, 0.95)
Zidovudine2 200 three times
daily, 7 days		 1000 threetimes
daily,7 days		 12 1.06
(0.91, 1.25)		 1.05
(0.86, 1.28)		 1.02
(0.77, 1.35)
Zidovudine/
Lamivudine(3TC)2		 200/150 three
times daily,7days		 800 three times
daily, 7 days		 6, 95 1.05
(0.83, 1.33)		 1.04
(0.67, 1.61)		 0.98
(0.56, 1.73)
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
1 Relative to indinavir 800 mg three times daily alone.
2 Study conducted in HIV-positive subjects.
3 Comparison to historical data on 16 subjects receiving indinavir alone.
4 95% CI.5 Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.

Table 3 Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)


Coadministered drug Dose of
Coadministered drug
(mg)		 Dose of CRIXIVAN
(mg)		 n Ratio (with/without CRIXIVAN) of Coadministered Drug
Pharmacokinetic Parameters
(90% CI); No Effect =1.00
        C max AUC C min
Clarithromycin 500 twice daily, 7 days 800 three times
daily, 7 days		 12 1.19
(1.02, 1.39)		 1.47
(1.30, 1.65)		 1.97
(1.58, 2.46)
n=11
Efavirenz 200 once daily, 14
days		 800 three times
daily, 14 days		 20 No significant
change		 No significant
change		 --
Ethinyl Estradiol
(ORTHO-NOVUM 1/35)1		 35 mcg, 8 days 800 three times
daily, 8 days		 18 1.02
(0.96, 1.09)		 1.22
(1.15, 1.30)		 1.37
(1.24, 1.51)
Isoniazid 300 once daily in the
morning, 8 days		 800 three times
daily, 8 days		 11 1.34
(1.12, 1.60)		 1.12
(1.03, 1.22)		 1.00
(0.92, 1.08)
Methadone2 20-60 once
daily in the
morning, 8 days		 800 three times
daily, 8 days		 12 0.93
(0.84, 1.03)		 0.96
(0.86, 1.06)		 1.06
(0.94, 1.19)
Norethindrone
(ORTHO-NOVUM 1/35)1		 1 mcg, 8 days 800 three times
daily, 8 days		 18 1.05
(0.95, 1.16)		 1.26
(1.20, 1.31)		 1.44
(1.32, 1.57)
Rifabutin
*150 mg once daily in themorning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone		 150 once daily in the
morning, 10 days		 800 three times
daily, 10 days		 14 1.29
(1.05, 1.59)		 1.54
(1.33, 1.79)		 1.99
(1.71, 2.31)
300 once daily in the
morning, 10 days		 800 three times
daily, 10 days		 10 2.34
(1.64, 3.35)		 2.73
(1.99, 3.77)		 3.44
(2.65, 4.46)
n=9
Ritonavir 100 twice daily, 14
days		 800 twice daily, 14
days		 10, 43 1.61
(1.13, 2.29)		 1.72
(1.20, 2.48)		 1.62
(0.93, 2.85)
200 twice daily, 14
days		 800 twice daily, 14
days		 9, 53 1.19
(0.85, 1.66)		 1.96
(1.39, 2.76)		 4.71
(2.66, 8.33)
n=9, 4
Saquinavir
            
  Hard gel formulation 600 single dose 800 three times
daily, 2 days		 6 4.7
(2.7, 8.1)		 6.0
(4.0, 9.1)		 2.9
(1.7, 4.7)4
  Soft gel formulation 800 single dose 800 three times
daily, 2 days		 6 6.5
(4.7, 9.1)		 7.2
(4.3, 11.9)		 5.5
(2.2, 14.1)4
  Soft gel formulation 1200 single dose 800 three times
daily, 2 days		 6 4.0
(2.7, 5.9)		 4.6
(3.2, 6.7)		 5.5
(3.7, 8.3)4
Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction.
Stavudine5 40 twice daily, 7 days 800 three times
daily, 7
days		 13 0.86
(0.73, 1.03)		 1.21
(1.09, 1.33)		 Not Done
Theophylline 250 single dose
(on Days 1 and 7)		 800 three times
daily, 6 days (Days 2 to 7)		 12, 43 0.88
(0.76, 1.03)		 1.14
(1.04, 1.24)		 1.13
(0.86, 1.49)
n=7, 3
Trimethoprim/ Sulfamethoxazole
  Trimethoprim		 800 Trimethoprim/
160 Sulfamethoxazole
q12h, 7 days		 400 q6h, 7 days 12 1.18
(1.05, 1.32)		 1.18
(1.05, 1.33)		 1.18
(1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
  Sulfamethoxazole		 800 Trimethoprim/
160 Sulfamethoxazole
q12h, 7 days		 400 q6h, 7 days 12 1.01
(0.95, 1.08)		 1.05
(1.01, 1.09)		 1.05
(0.97, 1.14)
Vardenafil 2.5 single dose 800 three times daily 18 See text below for discussion of interaction.
Zidovudine5 200 three times daily,
7 days		 1000 three times
daily, 7 days		 12 0.89
(0.73, 1.09)		 1.17
(1.07, 1.29)		 1.51
(0.71, 3.20)
n=4
Zidovudine/Lamivudine5
Zidovudine		 200/150 three
times daily, 7days		 800 three times
daily, 7 days		 6, 73 1.23
(0.74, 2.03)		 1.39
(1.02, 1.89)		 1.08
(0.77, 1.50)n=5, 5
Zidovudine/Lamivudine5
Lamivudine		 200/150 three
times daily,
7days		 800 three times
daily, 7 days		 6, 73 0.73
(0.52, 1.02)		 0.91
(0.66, 1.26)		 0.88
(0.59, 1.33)
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
1 Registered trademark of Ortho Pharmaceutical Corporation
2 Study conducted in subjects on methadone maintenance.
3 Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.
4 C6hr
5 Study conducted in HIV-positive subjects.
Brand Name: Crixivan
Generic Name: Indinavir Sulfate
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