CRIXIVAN 200 mg and 400 mg hard capsules

1. Name Of The Medicinal Product

CRIXIVAN 200 mg hard capsules

CRIXIVAN 400 mg hard capsules

2. Qualitative And Quantitative Composition

CRIXIVAN 200 mg:

Each hard capsule contains indinavir sulphate corresponding to 200 mg of indinavir.

Excipient: Each 200 mg capsule contains 74.8 mg lactose

CRIXIVAN 400 mg:

Each hard capsule contains indinavir sulphate corresponding to 400 mg of indinavir.

Excipient: Each 400 mg capsule contains 149.6 mg lactose

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Hard capsule.

CRIXIVAN 200 mg: The capsules are semi-translucent white and coded 'CRIXIVAN™ 200 mg' in blue.

CRIXIVAN 400 mg: The capsules are semi-translucent white and coded 'CRIXIVAN™ 400 mg' in green.

4. Clinical Particulars

4.1 Therapeutic Indications

CRIXIVAN is indicated in combination with antiretroviral nucleoside analogues for the treatment of HIV-1 infected adults, adolescents, and children 4 years of age and older. In adolescents and children, the benefit of indinavir therapy versus the increased risk of nephrolithiasis should particularly be considered (see section 4.4).

4.2 Posology And Method Of Administration

CRIXIVAN should be administered by physicians who are experienced in the treatment of HIV infection. On the basis of current pharmacodynamic data, indinavir must be used in combination with other antiretroviral agents. When indinavir is administered as monotherapy resistant viruses rapidly emerge (see section 5.1).

Posology

Adults

The recommended dose of indinavir is 800 mg orally every 8 hours.

Data from published studies suggest that CRIXIVAN 400 mg in combination with ritonavir 100 mg, both administered orally twice daily, may be an alternative dosing regimen. The suggestion is based on limited published data (see section 5.2).

A dose reduction of indinavir to 600 mg every 8 hours should be considered when administering itraconazole or ketoconazole concurrently (see section 4.5).

Children and adolecents (4 to 17 years of age)

The recommended dose of CRIXIVAN for patients 4 to 17 years of age is 500 mg/m² (dose adjusted from calculated body surface area [BSA] based on height and weight) orally every 8 hours (see table below). This dose should not exceed the equivalent of the adult dose of 800 mg every 8 hours. CRIXIVAN hard capsules should only be given to children who are able to swallow hard capsules.

Paediatric dose (500 mg/m²) to be administered every 8 hours

Body Surface Area (m2)	CRIXIVAN dose Every 8 hours (mg)
0.50	300
0.75	400
1.00	500
1.25	600
1.50	800

Special populations

Hepatic impairment

In patients with mild-to-moderate hepatic impairment due to cirrhosis, the dose of indinavir should be reduced to 600 mg every 8 hours. The recommendation is based on limited pharmacokinetic data (see section 5.2). Patients with severe hepatic impairment have not been studied; therefore, no dosing recommendations can be made (see section 4.4).

Renal impairment

Safety in patients with impaired renal function has not been studied; however, less than 20 % of indinavir is excreted in the urine as unchanged medicinal product or metabolites (see section 4.4).

Paediatric population

The safety and efficacy of CRIXIVAN in children under the age of 4 years have not been established (see section 5.1 and 5.2). Currently available data are described in sections 4.8 and 5.1, but no recommendation on a posology can be made for children under the age of 4 years.

Method of administration

The hard capsules should be swallowed whole.

Since CRIXIVAN must be taken at intervals of 8 hours, a schedule convenient for the patient should be developed. For optimal absorption, CRIXIVAN should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, CRIXIVAN may be administered with a low-fat, light meal.

If common-administered with ritonavir, CRIXIVAN may be administered with or without food.

To ensure adequate hydration, it is recommended that adults drink at least 1.5 litres of liquids during the course of 24 hours. It is also recommended that children who weigh less than 20 kg drink at least 75 ml/kg/day and that children who weigh 20 to 40 kg drink at least 50 ml/kg/day.

Medical management in patients with one or more episodes of nephrolithiasis must include adequate hydration and may include temporary interruption of therapy (e.g., 1 to 3 days) during the acute episode of nephrolithiasis or discontinuation of therapy (see section 4.4).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Indinavir with or without ritonavir should not be administered concurrently with medicinal products with narrow therapeutic windows and which are substrates of CYP3A4. Inhibition of CYP3A4 by both CRIXIVAN and ritonavir could result in elevated plasma concentrations of these medicines, potentially causing serious or life-threatening reactions (see section 4.5).

CRIXIVAN with or without ritonavir must not be administered concurrently with amiodarone, terfenadine, cisapride, astemizole, alprazolam, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), pimozide, ergot derivatives, simvastatin or lovastatin (see section 4.4).

Combination of rifampicin with CRIXIVAN with or without concomitant low-dose ritonavir is contraindicated (see section 4.5). Concurrent use of indinavir with herbal preparations containing St John's wort (Hypericum perforatum) is contraindicated (see section 4.5).

In addition, indinavir with ritonavir should not be administered with alfuzosin, meperidine, piroxicam, propoxyphene, bepridil, encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine, clorazepate, diazepam, estazolam and flurazepam.

Indinavir should not be given with ritonavir to patients with decompensated liver disease as ritonavir is principally metabolised and eliminated by the liver (see section 4.4).

When CRIXIVAN is used with ritonavir, consult the Summary of Product Characteristics of ritonavir for additional contraindications.

4.4 Special Warnings And Precautions For Use

Nephrolithiasis and tubulointerstitial nephritis

Nephrolithiasis has occurred with indinavir therapy in adult and paediatric patients. The cumulative frequency of nephrolithiasis is substantially higher in paediatric patients (29%) than in adult patients (12.4%; range across individual trials: 4.7% to 34.4%). The cumulative frequency of nephrolithiasis events increases with increasing exposure to CRIXIVAN; however, the risk overtime remains relatively constant. Physicians considering the use of indinavir in paediatric patients without other protease inhibitor options should be aware of the limited data available in this population and the increased risk of nephrolithiasis. In some cases, nephrolithiasis has been associated with renal insufficiency or acute renal failure; in the majority of these cases renal insufficiency and acute renal failure were reversible. If signs and symptoms of nephrolithiasis, including flank pain with or without haematuria (including microscopic haematuria) occur, temporary interruption of therapy (e.g. for 1-3 days) during the acute episode of nephrolithiasis or discontinuation of therapy may be considered. Paediatric patients who experience flank pain should be evaluated for the possibility of nephrolithiasis. Evaluation may consist of urinalysis, serum BUN and creatinine, and ultrasound of the bladder and kidneys. The long-term effects of nephrolithiasis in paediatric patients are unknown. Adequate hydration is recommended in all patients on indinavir (see section 4.2 and 4.8).

Medical management in patients with one or more episodes of nephrolithiasis must include adequate hydration and may include temporary interruption of therapy (e.g., 1 to 3 days) during the acute episode of nephrolithiasis or discontinuation of therapy.

Cases of interstitial nephritis with medullary calcification and cortical atrophy have been observed in patients with asymptomatic severe leucocyturia (>100 cells/high power field). In patients at increased risk such as children, urinary screening should be considered. If persistent severe leucocyturia is found, further investigation might be warranted.

Medicinal product interactions

Indinavir should be used cautiously with other medicinal products that are potent inducers of CYP3A4. Co-administration may result in decreased plasma concentrations of indinavir and as a consequence an increased risk for suboptimal treatment and facilitation of development of resistance (see section 4.5).

If indinavir is given with ritonavir, the potential interaction may be increased. The Interactions section of the SPC for ritonavir should also be consulted for information about potential interactions.

Atazanavir as well as indinavir are associated with indirect (unconjugated) hyperbilirubinemia due to inhibition of UDP-glucuronosyltransferase (UGT). Combinations of atazanavir with or without ritonavir and CRIXIVAN have not been studied and co-administration of these medicinal products is not recommended due to risk of worsening of these adverse reactions.

Concomitant use of indinavir with lovastatin or simvastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis. Based on an interaction study with lopinavir/ritonavir, combination of rosuvastatin and protease inhibitors is not recommended. Caution must also be exercised if indinavir is used concurrently with atorvastatin. The interaction of indinavir or indinavir/ritonavir with pravastatin or fluvastatin is not known (see section 4.5).

Co-administration of CRIXIVAN with sildenafil, tadalafil and vardenafil (PDE5 inhibitors) are expected to substantially increase the plasma concentrations of these compounds and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism (see section 4.5).

Acute haemolytic anaemia

Acute haemolytic anaemia has been reported which in some cases was severe and progressed rapidly. Once a diagnosis is apparent, appropriate measures for the treatment of haemolytic anaemia should be instituted which may include discontinuation of indinavir.

Hyperglycaemia

New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been reported in patients receiving protease inhibitors (PIs). In some of these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many 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.

Fat redistribution

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 PIs and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicinal product 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 (see section 4.8).

Liver disease

The safety and efficacy of indinavir has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information 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.

An increased incidence of nephrolithiasis has been observed in patients with underlying liver disorders when treated with indinavir.

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 mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Patients with coexisting conditions

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with PIs. In some patients additional factor VIII was given. In more than a half of the reported cases, treatment with PIs was continued or re-introduced 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 made aware of the possibility of increased bleeding.

Patients with mild-to-moderate hepatic insufficiency due to cirrhosis will require a dose reduction of indinavir due to decreased metabolism of indinavir (see section 4.2). Patients with severe hepatic impairment have not been studied. In the absence of such studies, caution should be exercised as increased levels of indinavir may occur.

Safety in patients with impaired renal function has not been studied; however, less than 20 % of indinavir is excreted in the urine as unchanged medicinal product or metabolites (see section 4.2).

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.

Lactose

This medicinal product contains 299.2 mg of lactose in each 800 mg dose (maximum single dose).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults. The relevance of the results from these studies in paediatric patients is unknown.

The metabolism of indinavir is mediated by the cytochrome P450 enzyme CYP3A4. Therefore, other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of indinavir. Similarly, indinavir might also modify the pharmacokinetics of other substances that share this metabolic pathway. Boosted indinavir (indinavir with ritonavir) may have additive pharmacokinetic effects on substances that share the CYP3A4 pathway as both ritonavir and indinavir inhibit the cytochrome P450 enzyme CYP3A4.

Indinavir with or without ritonavir should not be administered concurrently with medicinal products with narrow therapeutic windows and which are substrates of CYP3A4. Inhibition of CYP3A4 by both CRIXIVAN and ritonavir could result in elevated plasma concentrations of these medicines, potentially causing serious or life-threatening reactions. CRIXIVAN with or without ritonavir should not be administered concurrently with amiodarone, terfenadine, cisapride, astemizole, alprazolam, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see Table 1 and 2 below), pimozide, ergot derivatives, simvastatin or lovastatin. In addition, indinavir with ritonavir should not be administered with alfuzosin, meperidine, piroxicam, propoxyphene, bepridil, encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine, clorazepate, diazepam, estazolam and flurazepam.

Concurrent use of indinavir with rifampicin or herbal preparations containing St John's wort (Hypericum perforatum) is contraindicated.

Medicinal products listed above are not repeated in Table 1 and 2 unless specific interaction data is available.

Refer also to sections 4.2 and 4.3.

Table 1. Interactions and dose recommendations with other medical products - UNBOOSTED INDINAVIR

Interactions between indinavir and other medicinal products are listed in the tables below (increase is indicated as "↑", decrease as "

Medicinal products by therapeutic areas	Interaction	Recommendations concerning co-administration
ANTI-INFECTIVES
Antiretrovirals
NRTIs
Didanosine Formulation with buffer	No formal interaction study has been performed. A normal (acidic) gastric pH may be necessary for optimum absorption of indinavir whereas acid rapidly degrades didanosine which is formulated with buffering agents to increase pH. Antiretroviral activity was unaltered when didanosine was administered 3 hours after treatment with indinavir.	Indinavir and didanosine formulations containing buffer should be administered at least one hour apart on an empty stomach.
Didanosine enteric-coated 400 mg SD (Indinavir 800 mg SD)	Indinavir: ↔ (Relative to Indinavir 800 mg SD alone) Didanosine: ↔	Can be administered without any restrictions with respect to time of administration or food.
Stavudine 40 mg BID (Indinavir 800 mg TID)	Indinavir AUC: ↔ Indinavir Cmin : ↔ (Relative to Indinavir 800 mg TID alone) Stavudine AUC: ↑ 21% Stavudine Cmin: not evaluated	Indinavir and NRTIs can be co-administered without dose adjustment.
Zidovudine 200 mg TID (Indinavir 1000 mg TID)	Indinavir AUC: ↔ Indinavir Cmin: ↔ (Relative to Indinavir 1000 mg TID alone) Zidovudine AUC: ↔ Zidovudine Cmin: ↑ 51%
Zidovudine/Lamivudine 200/150 mg TID (Indinavir 800 mg TID)	Indinavir AUC: ↔ Indinavir Cmin: ↔ (Relative to Indinavir 800 mg TID alone) Zidovudine AUC: ↑ 39% Zidovudine Cmin: ↔ Lamivudine AUC: ↔ Lamivudine Cmin: ↔
NNRTIs
Delavirdine 400 mg TID (Indinavir 600 mg TID)   Delavirdine 400 mg TID Indinavir 400 mg TID	Indinavir AUC: ↑ 53% Indinavir Cmin ↑ 298% (Relative to Indinavir 800 mg TID alone) Indinavir AUC: ↔ Indinavir Cmin: ↑ 118% (Relative to Indinavir 800 mg TID alone) Delavirdine: ↔	Dose reduction of CRIXIVAN to 400-600 mg every 8 hours should be considered.
Efavirenz 600 mg QD (Indinavir 1000 mg TID)     Efavirenz 200 mg QD (Indinavir 800 mg TID)	Indinavir AUC: Indinavir Cmin: (Relative to Indinavir 800 mg TID alone) An increased dose (1000mg TID) of indinavir does not compensate for the inducing effect of efavirenz. Indinavir AUC: Indinavir Cmin: Efavirenz AUC: ↔	No specific dose recommendation can be given.
Nevirapine 200 mg BID (Indinavir 800 mg TID)	Indinavir AUC: Nevirapine: ↔ (CYP3A induction)	A dose increase of indinavir to 1000 mg every 8 hours should be considered if given with nevirapine.
PIs
Amprenavir 1200 mg BID (Indinavir 1200 mg BID)	Amprenavir AUC: ↑ 90% Indinavir:↔	The appropriate doses for this combination, with respect to efficacy and safety, have not been established.
Atazanavir	Interaction not studied	Combination of atazanavir with or without ritonavir and CRIXIVAN are not recommended due to increased risk of hyperbilirubinemia (see section 4.4).
Ritonavir 100 mg BID (Indinavir 800 mg BID)       Ritonavir 200 mg BID (Indinavir 800 mg BID)       Ritonavir 400 mg BID (Indinavir 800 mg BID)     Ritonavir 400 mg BID (Indinavir 400 mg BID)     Ritonavir 100 mg BID (Indinavir 400 mg BID)	Indinavir AUC24hr:↑ 178% Indinavir Cmin:↑11-fold; (Relative to Indinavir 800 mg TID alone*) Ritonavir AUC: ↑ 72% Ritonavir Cmin: ↑ 62% Indinavir AUC24hr:↑266% Indinavir Cmin:↑24-fold; (Relative to Indinavir 800 mg TID alone*) Ritonavir AUC: ↑ 96% Ritonavir Cmin: ↑ 371% Indinavir AUC24hr:↑220% Indinavir Cmin:↑ 24-fold (Relative to Indinavir 800 mg TID alone*) Ritonavir AUC24hr: ↔ Indinavir AUC24hr:↑68% Indinavir Cmin: ↑ 10-fold (Relative to Indinavir 800 mg TID alone*) Ritonavir AUC24hr: ↔ Indinavir AUC and Cmin: ↔ (Relative to Indinavir 800 mg TID alone*) (*) historical controls	The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Preliminary clinical data suggest that CRIXIVAN 400 mg in combination with ritonavir 100 mg, both administered orally twice daily, may be an alternative dosing regimen (see section 5.2). A boosted dose of 800 mg indinavir/100 mg ritonavir twice daily results in increased risk of adverse events.
Saquinavir 600 mg SD (hard gel capsule formulation) (Indinavir 800 mg TID)   Saquinavir 800 mg SD (soft gel capsule formulation) (Indinavir 800 mg TID)   Saquinavir 1200 mg SD (soft gel capsule formulation) (Indinavir 800 mg TID)	Saquinavir AUC: ↑ 500% Saquinavir Cmin: ↑ 190% (Relative to saquinavir 600 mg SD (hard gel formulation) alone) Saquinavir AUC: ↑ 620% Saquinavir Cmin: ↑ 450% (Relative to saquinavir 800 mg SD (soft gel formulation) alone) Saquinavir AUC: ↑ 360% Saquinavir Cmin: ↑ 450% (Relative to saquinavir 1200 mg (soft gel formulation) alone) The design of the study does not allow for definitive evaluation of the effect of saquinavir on indinavir, but suggests there is less than a two-fold increase in indinavir AUC8h during co-administration with saquinavir.	The appropriate doses for this combination, with respect to efficacy and safety, have not been established.
Antibiotics
Sulphamethoxazole/ Trimethoprim 800 mg/160 mg BID (Indinavir 400 mg QID)	Indinavir AUC and Cmin: ↔ (Relative to Indinavir 400 mg QID alone) Sulphamethoxazole AUC and Cmin: ↔	Indinavir and sulphamethoxazole/ trimethoprim can be co-administered without dose adjustment.
Antifungals
Fluconazole 400 mg QD (Indinavir 1000 mg TID)	Indinavir AUC: Indinavir Cmin: ↔ (Relative to Indinavir 1000 mg TID alone)	Indinavir and fluconazole can be co-administered without dose adjustment.
Itraconazole 200 mg BID (Indinavir 600 mg TID)	Indinavir AUC: ↔ Indinavir Cmin: ↑ 49% (Relative to Indinavir 800 mg TID alone)	Dose reduction of CRIXIVAN to 600 mg every 8 hours is recommended with administering itraconazole concurrently.
Ketoconazole 400 mg QD (Indinavir 600 mg TID)   Ketoconazole 400 mg QD (Indinavir 400 mg TID)	Indinavir AUC: Indinavir Cmin: ↑ 29% (Relative to Indinavir 800 mg TID alone) Indinavir AUC Indinavir Cmin (Relative to Indinavir 800 mg TID alone)	Dose reduction of CRIXIVAN to 600 mg every 8 hours should be considered.
Anti-Mycobacterial
Isoniazid 300 mg QD (Indinavir 800 mg TID)	Indinavir AUC and Cmin: ↔ (Relative to Indinavir 800 mg TID alone) Isoniazid AUC and Cmin: ↔	Indinavir and isoniazid can be co-administered without dose adjustment.
Rifabutin 300 mg QD (Indinavir 800 mg TID)         Rifabutin 150 mg QD (Indinavir 800 mg TID)	Indinavir AUC: Indinavir Cmin : (Relative to Indinavir 800 mg TID alone) Rifabutin AUC: ↑ 173% Rifabutin Cmin: ↑ 244% (Relative to rifabutin 300 mg QD alone) Indinavir AUC: Indinavir Cmin: (Relative to Indinavir 800 mg TID alone) Rifabutin AUC*: ↑ 54% Rifabutin Cmin*: ↑ 99% (*Relative to rifabutin 300 mg QD alone. No data has been obtained comparing rifabutin 150 mg QD in combination with indinavir 800 mg TID with a reference dose of 150 mg rifabutin alone)	Dose reduction of rifabutin and dose increase of CRIXIVAN has not been confirmed in clinical studies. Therefore co-administration is not recommended. If rifabutin treatment is required, alternative agents for treating HIV infection should be sought.
Rifampicin 600 mg QD (Indinavir 800 mg TID)	Indinavir AUC: (Relative to Indinavir 800 mg TID alone) This effect is due to an induction of CYP3A4 by rifampicin.	The use of rifampicin with indinavir is contraindicated.
ANALGESICS
Methadone 20-60 mg QD (Indinavir 800 mg TID)	Indinavir AUC: ↔ (Relative to Indinavir 800 mg TID historical controls) Methadone AUC and Cmin: ↔	Indinavir and methadone can be co-administered without dose adjustment.
ANTIARRHYTHMICS
Quinidine 200 mg SD (Indinavir 400 mg SD)	Indinavir AUC and Cmin: ↔ (Relative to Indinavir 400 mg SD) ↑ Quinidine concentration expected (CYP3A4 inhibition by indinavir)	Caution is warranted and therapeutic concentration monitoring is recommended for quinidine when co-administered with CRIXIVAN. The use of indinavir/ritonavir with quinidine is contraindicated.
ANTIASTHMATIC
Theophylline 250 mg SD (Indinavir 800 mg TID)	Theophylline AUC and Cmin: ↔	Indinavir and theophylline can be co-administered without dose adjustment.
ANTICOAGULANT
Warfarin	Not studied, combined administration may result in increased warfarin levels.	Dose adjustment of warfarin may be required.
ANTICONVULSANTS
Carbamazepine, phenobarbital phenytoin	Indinavir inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of these anticonvulsants. Concomitant use of medicinal products that are inducers of CYP3A4, such as carbamazepine, phenobarbital and phenytoin may reduce indinavir plasma concentrations.	Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with indinavir.
ANTIDEPRESSANTS
Venlafaxine 50 mg TID (Indinavir 800 mg SD)	Indinavir AUC: (Relative to Indinavir 800 mg SD alone) Venlafaxine and active metabolite O-desmethyl-venlafaxine: ↔	The clinical significance of this finding is unknown.
CALCIUM CHANNEL BLOCKERS
Dihydropyridine: e.g., felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blocker concentration. Calcium channel blockers are metabolised by CYP3A4 which is inhibited by indinavir.	Caution is warranted and clinical monitoring of patients is recommended.
HERBAL MEDICATIONS
St. John's wort (Hypericum perforatum) 300 mg TID (Indinavir 800 mg TID)	Indinavir AUC: Indinavir Cmin: (Relative to Indinavir 800 mg TID alone) Reduction in indinavir concentrations due to induction of medicinal product metabolising and/or transport proteins by St. John's wort.	Herbal preparations containing St. John's wort are contraindicated with CRIXIVAN. If a patient is already taking St. John's wort, stop St. John's wort, check viral levels and if possible indinavir levels. Indinavir levels may increase on stopping St. John's wort, and the dose of CRIXIVAN may need adjusting. The inducing effect may persist up to 2 weeks after cessation of treatment with St. John's wort.
HISTAMINE H2 ANTAGONIST
Cimetidine 600 mg BID (Indinavir 400 mg SD)	Indinavir AUC and Cmin: ↔ (Relative to Indinavir 400 mg SD alone)	Indinavir and cimetidine can be co-administered without dose adjustment.
HMG-CoA REDUCTASE INHIBITIORS
Lovastatin, simvastatin	Indinavir inhibits CYP3A4 and as a result is expected to markedly increase the plasma concentrations of these HMG-CoA reductase inhibitors, which are highly dependent on CYP3A4 metabolism.	Combination contraindicated due to an increased risk of myopathy including rhabdomyolysis.
Rosuvastatin	Interaction not studied. Interaction study with Lopinavir/ritonavir + rosuvastatin: Rosuvastatin AUC ↑ 2.08 -fold Rosuvastatin Cmax↑ 4.66 -fold (Mechanism unknown)