Crixivan

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 



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1. NAME OF THE MEDICINAL PRODUCT

CRIXIVAN 200 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect
Each 200 mg capsule contains 74.8 mg lactose.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Hard capsule.

The capsules are semi–translucent white and coded ‘CRIXIVAN ™ 200 mg’ in blue. 

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

CRIXIVAN is indicated in combination with antiretroviral nucleoside analogues for the treatment of 
HIV–1 infected adults.

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
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).

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).

 



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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 in children above the age of 4 years are described in 
sections 4.8, 5.1, and 5.2.

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 co-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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 should not be administered concurrently with amiodarone, 
terfenadine, cisapride, astemizole, quetiapine, 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 must not be administered with alfuzosin, meperidine, piroxicam, 
propoxyphene, bepridil, encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine, 
clorazepate, diazepam, estazolam and flurazepam.

Indinavir must not be given with ritonavir to patients with decompensated liver disease as ritonavir is 
principally metabolized 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 patients with a cumulative frequency of 
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 over time remains 
relatively constant. 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 

 



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(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. 
Evaluation may consist of urinalysis, serum BUN and creatinine, and ultrasound of the bladder and 
kidneys. Adequate hydration is recommended in all patients on indinavir (see sections 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, urinary screening should be considered. If persistent severe leucocyturia is found, further 
investigation might be warranted.

Medicinal products 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).

HIV Transmission
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent 
transmission should be taken in accordance with national guidelines.

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.

Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

 



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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.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment.

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. 

 



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4.5 Interaction with other medicinal products and other forms of interaction

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, quetiapine, 
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 “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”, once daily as 
“QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").

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.

 



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Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

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 1,000 mg TID)

Indinavir AUC: 
Indinavir Cmin: 
(Relative to Indinavir 1,000 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 1,000 mg TID)

Efavirenz 200 mg QD
(Indinavir 800 mg TID)

Indinavir AUC:  46 %
Indinavir Cmin:  57 %
(Relative to Indinavir 800 mg TID alone)
An increased dose (1,000 mg TID) of indinavir 
does not compensate for the inducing effect of 
efavirenz.

Indinavir AUC:  31 %
Indinavir Cmin:  40 %

Efavirenz AUC: 

No specific dose 
recommendation can be 
given.

Nevirapine 200 mg BID
(Indinavir 800 mg TID)

Indinavir AUC:  28 %
Nevirapine:  (CYP3A induction)

A dose increase of indinavir 
to 1,000 mg every 8 hours 
should be considered if 
given with nevirapine.

PIs
Amprenavir 1,200 mg BID
(Indinavir 1,200 mg BID)

Amprenavir AUC: ↑ 90 %
Indinavir: ↔ 

The appropriate doses for 
this combination, with 
respect to efficacy and 
safety, have not been 
established.

 



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Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

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.

 



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Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

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 1,200 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 1,200 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 1,000 mg TID)

Indinavir AUC: ↓ 24 % 
Indinavir Cmin: 
(Relative to Indinavir 1,000 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: ↓ 20 %
Indinavir Cmin: ↑ 29 %
(Relative to Indinavir 800 mg TID alone)
Indinavir AUC ↓ 56 %
Indinavir Cmin ↓ 27 %
(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.

 



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Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

Rifabutin 300 mg QD
(Indinavir 800 mg TID)

Rifabutin 150 mg QD
(Indinavir 800 mg TID)

Indinavir AUC ↓ 34 %
Indinavir Cmin : ↓ 39 %
(Relative to Indinavir 800 mg TID alone)

Rifabutin AUC: ↑ 173 %
Rifabutin Cmin: ↑ 244 %
(Relative to rifabutin 300 mg QD alone)

Indinavir AUC: ↓ 32 %
Indinavir Cmin: ↓ 40 %
(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:  92 %
(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 
coadministered 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:  28 %
(Relative to Indinavir 800 mg SD alone)
Venlafaxine and active metabolite O-
desmethyl-venlafaxine: 

The clinical significance of 
this finding is unknown.

 



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Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

ANTIPSYCHOTICS
Quetiapine Not studied. Due to CYP3A inhibition by 

indinavir, concentrations
of quetiapine are expected to increase.

Concomitant administration 
of indinavir and quetiapine 
may increase plasma 
concentrations of quetiapine 
leading to quetiapine-related 
toxicity, including coma. 
Co-administration of 
quetiapine with indinavir is 
contraindicated (see 
section 4.3).

CALCIUM CHANNEL BLOCKERS
Dihydropyridine: e.g., 
felodipine, nifedipine, 
nicardipine

 dihydropyridine calcium channel blocker 
concentration

Calcium channel blockers are metabolized 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:  54 %
Indinavir Cmin: ↓ 81 %
(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 INHIBITORS

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)

Combination not 
recommended

Atorvastatin  atorvastatin concentration
Atorvastatin is less dependent on CYP3A4 for 
metabolism than lovastatin or simvastatin

Use the lowest possible 
dose of atorvastatin with 
careful monitoring. Caution 
is advised.

 



12

Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

Pravastatin, fluvastatin Interaction not studied
Metabolism of pravastatin and fluvastatin is not 
dependent on CYP3A4. Interaction via effects 
on transport proteins cannot be excluded.

Interaction unknown. If no 
alternative treatment is 
available, use with careful 
monitoring.

IMMUNOSUPPRESSIVES
Cyclosporine A Cyclosporine A (CsA) levels markedly increase 

in patients on PIs, including indinavir.
CsA levels require 
progressive dose adjustment 
using therapeutic medicinal 
product monitoring.

ORAL CONTRACEPTIVES
Norethindrone/ethinyl estradiol
1/35 1 mcg QD
(Indinavir 800 mg TID)

Norethindrone AUC: ↑ 26 %
Norethindrone Cmin: ↑ 44 %

Indinavir and 
norethindrone/ethinyl 
estradiol 1/35 can be co-
administered without dose 
adjustment.

PDE5 INHIBITOR
Sildenafil 25 mg SD
(Indinavir 800 mg TID)

Indinavir AUC:  11 %
Sildenafil AUC  340 %

Coadministration of CRIXIVAN with sildenafil 
is likely to result in an increase of sildenafil by 
competitive inhibition of metabolism.

Sildenafil dose should not 
exceed a maximum of 
25 mg in a 48-hour period 
in patients receiving 
concomitant indinavir 
therapy.

Vardenafil 10 mg SD
(Indinavir 800 mg TID)

Vardenafil AUC: ↑ 16-fold

Coadministration of CRIXIVAN with 
vardenafil is likely to result in an increase of 
vardenafil by competitive inhibition of 
metabolism.

Vardenafil dose should not 
exceed a maximum of 
2.5 mg in a 24-hour period 
in patients receiving 
concomitant indinavir 
therapy.

Tadalafil Interaction not studied

Coadministration of CRIXIVAN with tadalafil 
is likely to result in an increase of tadalafil by 
competitive inhibition of metabolism.

Tadalafil dose should not 
exceed a maximum of 
10 mg in a 72 hour period in 
patients receiving 
concomitant indinavir 
therapy.

SEDATIVES/HYPNOTICS
Midazolam (parenteral) Not studied, combined administrations are 

expected to significantly increase 
concentrations of midazolam, particularly when 
midazolam is given orally.

Midazolam is extensively metabolized by 
CYP3A4.

CRIXIVAN and oral 
midazolam should not be 
coadministered (see 
section 4.3). Caution should 
be used with 
coadministration of 
CRIXIVAN and parenteral 
midazolam. If CRIXIVAN 
is coadministered with 
parenteral midazolam, it 
should be done in an 
intensive care unit with 
close clinical monitoring in 
case of respiratory 
depression and/or prolonged 
sedation. Dose adjustment 
for midazolam should be 
considered, especially if 
more than a single dose of 
midazolam is administered.

 



13

Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

STEROIDS
Dexamethasone Interaction not studied

 dexamethasone exposure expected (CYP3A 
inhibition). 
 indinavir plasma concentrations may be 
expected (CYP3A induction).

Careful monitoring of 
therapeutic and adverse 
effects is recommended 
when dexamethasone is 
concomitantly administered 
with indinavir.

Table 2. Interactions and dose recommendations with other medical products – INDINAVIR 
BOOSTED WITH RITONAVIR. No specific interaction studies have been performed with the 
boosted dose 400 mg indinavir with 100 mg ritonavir.

Interactions between indinavir/ritonavir and other medicinal products are listed in the tables below 
(increase is indicated as “↑”, decrease as “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”, 
once daily as “QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").

Medicinal products by 
therapeutic areas

Interaction Recommendations concerning 
co-administration

ANTI-INFECTIVES
Antiretrovirals
Amprenavir Amprenavir 1,200 mg BID AUC ↑90 % with 

800 mg TID indinavir alone (see Table 1).  
Amprenavir 600 mg BID AUC ↑ 64 % with 
100 mg BID ritonavir alone (relative to 
amprenavir 1,200 mg BID alone). Ritonavir 
increases the serum levels of amprenavir as a 
result of CYP3A4 inhibition.
There are no interaction data available on the 
coadministration of indinavir/ritonavir and 
amprenavir. 

The appropriate doses for this 
combination, with respect to 
efficacy and safety, have not 
been established.  Ritonavir
oral solution should not be co-
administered with amprenavir 
oral solution to children due to 
the risk of toxicity from 
excipients in the two 
formulations.

Efavirenz 600 mg QD
(Indinavir/ritonavir 800/100 
BID)

Indinavir AUC: 25 %
Indinavir Cmin ↓ 50 %
(Relative to Indinavir/ritonavir 800/100 BID 
alone)

Ritonavir AUC ↓ 36 %
Ritonavir Cmin: 39 %

Efavirenz AUC and Cmin : ↔

Dose increases of 
indinavir/ritonavir when given 
in combination with efavirenz 
have not been studied.

Anti-Mycobacterial
Rifabutin Interaction with indinavir/ritonavir not studied 

Decreased indinavir concentrations and 
increased rifabutin concentrations are 
expected.

No dose recommendations for 
indinavir/ritonavir with 
rifabutin could be given, 
therefore the combination is 
not recommended.  If rifabutin 
treatment is required, 
alternative agents for treating 
HIV infection should be 
sought.

 



14

Medicinal products by 
therapeutic areas

Interaction Recommendations concerning 
co-administration

Rifampicin Rifampicin is a strong CYP3A4 inducer and
has been shown to cause a 92 % decrease in 
indinavir AUC which 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.

The combination of rifampicin 
and CRIXIVAN with 
concomitant low-dose ritonavir
is contraindicated (see 
section 4.3).

Other Anti-infectives
Atovaquone Interaction with indinavir/ritonavir not studied 

Ritonavir induces glucuronidation and as a 
result is expected to decrease the plasma 
concentrations of atovaquone.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
atovaquone is concomitantly 
administered with 
indinavir/ritonavir.

Erythromycin, Itraconazole Interaction with indinavir/ritonavir not studied 
Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of erythromycin and 
itraconazole.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
erythromycin or itraconazole 
are concomitantly 
administered with 
indinavir/ritonavir.

Ketoconazole Interaction with indinavir/ritonavir not studied  
Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of ketoconazole. Co-
administration of ritonavir and ketoconazole 
caused an increased incidence of 
gastrointestinal and hepatic adverse events.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
ketoconazole is concomitantly 
administered with 
indinavir/ritonavir. A dose 
reduction of ketoconazole 
should be considered when co-
administered with 
indinavir/ritonavir.

ANALGESICS
Fentanyl Interaction with indinavir/ritonavir not studied 

Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of fentanyl.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when fentanyl 
is concomitantly administered 
with indinavir/ritonavir.

Methadone Interaction with indinavir/ritonavir not studied

There is no significant effect of unboosted 
indinavir on methadone AUC (see Table 1 
above).

Decreases in methadone AUC has been 
observed with other ritonavir-boosted protease 
inhibitors.
Ritonavir may induce glucuronidation of 
methadone.

Increased methadone dose may 
be necessary when 
concomitantly administered 
with indinavir/ritonavir. Dose 
adjustment should be 
considered based on the 
patient’s clinical response to 
methadone therapy.

Morphine Interaction with indinavir/ritonavir not studied 
Morphine levels may be decreased due to 
induction of glucuronidation by 
coadministered ritonavir.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
morphine is concomitantly 
administered with 
indinavir/ritonavir.

 



15

Medicinal products by 
therapeutic areas

Interaction Recommendations concerning 
co-administration

ANTIARRTHYMICS
Digoxin 0.4 mg SD
Ritonavir 200 mg BID

Interaction with indinavir/ritonavir not studied 
Digoxin AUC:  22 %

Ritonavir may increase 
digoxin levels due to 
modification of P-glycoprotein 
mediated digoxin efflux. 
Careful monitoring of digoxin 
levels is recommended when 
digoxin is concomitantly 
administered with 
indinavir/ritonavir.

ANTICOAGULANT
Warfarin
Ritonavir 400 mg BID

Interaction with indinavir/ritonavir not studied
R-warfarin levels may be decreased leading to 
reduced anticoagulation due to induction of 
CYP1A2 and CYP2C9 by ritonavir.

Anticoagulation parameters 
should be monitored when 
warfarin is coadministered 
with indinavir/ritonavir.

ANTICONVULSANTS
Carbamazepine Interaction with indinavir/ritonavir not studied 

Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of carbamazepine.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
carbamazepine is 
concomitantly administered 
with indinavir/ritonavir.

Divalproex, lamotrigine, 
phenytoin

Interaction with indinavir/ritonavir not studied 
Ritonavir induces oxidation by CYP2C9 and 
glucuronidation and as a result is expected to 
decrease the plasma concentrations of 
anticonvulsants.

Careful monitoring of serum 
levels or therapeutic effects is 
recommended when these 
medicines are concomitantly 
administered with 
indinavir/ritonavir. Phenytoin 
may decrease serum levels of 
ritonavir.

ANTIDEPRESSANTS
Trazodone 50 mg SD
Ritonavir 200 mg BID

Interaction with indinavir/ritonavir not studied 
Trazodone AUC:  2.4-fold
An increase in the incidence in trazodone-
related adverse events was noted when 
coadministered with ritonavir.

The combination of trazodone 
with indinavir/ritonavir should 
be used with caution, initiating 
trazodone at the lowest dose 
and monitoring for clinical 
response and tolerability.

ANTIHISTAMINES
Fexofenadine Interaction with indinavir/ritonavir not studied 

Ritonavir may modify P-glycoprotein 
mediated fexofenadine efflux when 
coadministered resulting in increased 
concentrations of fexofenadine. 

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
fexofenadine is concomitantly 
administered with 
indinavir/ritonavir.

Loratidine Interaction with indinavir/ritonavir not studied 
Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of loratidine.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
loratidine is concomitantly 
administered with 
indinavir/ritonavir.

CALCIUM CHANNEL BLOCKERS
Diltiazem 120 mg QD
(Indinavir/ritonavir 800/100 
BID)

Diltiazem AUC0-24hr:  43 %
Indinavir/ritonavir AUCs: 

Dose modification of calcium 
channel blockers should be 
considered when co-
administered with 
indinavir/ritonavir as it may
result in an increased response.

Amlodipine 5 mg QD
(Indinavir/ritonavir 800/100 
BID)

Amlodipine AUC0-24hr:  80 %
Indinavir/ritonavir AUCs: 

 



16

Medicinal products by 
therapeutic areas

Interaction Recommendations concerning 
co-administration

HMG-CoA REDUCTASE INHIBITORS  Same recommendations as for 
indinavir without ritonavir 
boosting (see Table 1).

IMMUNOSUPPRESSIVES
Cyclosporine A
(Indinavir/ritonavir 800/100 
BID)

Following initiation of indinavir/ritonavir 
800/100 BID or lopinavir/ritonavir 400/100 
BID, dose reduction of cyclosporine A to 
5-20 % of prior dose was needed to maintain 
cyclosporine A levels within therapeutic range 
in one study.

Cyclosporine A dose 
adjustments should be made 
according to measured 
cyclosporine A trough blood 
levels.

Tacrolimus Interaction with indinavir/ritonavir not studied 
Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of tacrolimus.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
tacrolimus is concomitantly 
administered with 
indinavir/ritonavir.

PDE5 INHIBITOR
Sildenafil, tadalafil Interaction not studied.  For sildenafil and tadalafil, 

same recommendations as for 
indinavir without ritonavir 
boosting (see Table 1).

Vardenafil Interaction not studied. Vardenafil dose should not 
exceed a maximum of 2.5 mg 
in a 72-hour period when 
given with a boosted protease 
inhibitor.

SEDATIVES/HYPNOTICS
Buspirone Interaction with indinavir/ritonavir not studied 

Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of buspirone.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
buspirone is concomitantly 
administered with 
indinavir/ritonavir.

Midazolam (parenteral) Interaction with indinavir/ritonavir 
Not studied, combined administrations are 
expected to significantly increase 
concentrations of midazolam, particularly 
when midazolam is given orally (CYP3A4 
inhibition).

CRIXIVAN with ritonavir and 
oral midazolam should not be 
coadministered (see 
section 4.3). Caution should be 
used with coadministration of 
CRIXIVAN with ritonavir and 
parenteral midazolam. If 
CRIXIVAN with ritonavir is 
coadministered with parenteral 
midazolam, it should be done 
in an intensive care unit with 
close clinical monitoring in 
case of respiratory depression 
and/or prolonged sedation. 
Dose adjustment for 
midazolam should be 
considered, especially if more 
than a single dose of 
midazolam is administered.

STEROIDS
Dexamethasone Interaction with indinavir/ritonavir not studied 

 dexamethasone exposure expected (CYP3A 
inhibition). 
 indinavir plasma concentrations may be 
expected (CYP3A induction).

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
dexamethasone is 
concomitantly administered 
with indinavir/ritonavir.

 



17

For information regarding diet or the effect of food on indinavir absorption (see sections 4.2 and 5.2).

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no adequate and well-controlled studies in pregnant patients. Indinavir should be used 
during pregnancy only if the potential benefit justifies the potential risk to the foetus. Given that 
substantially lower antepartum exposures have been observed in a small study of HIV-infected 
pregnant patients and the limited data in this patient population, indinavir use is not recommended in 
HIV-infected pregnant patients (see section 5.2). 

Hyperbilirubinaemia, reported predominantly as elevated indirect bilirubin, has occurred in 14 % of 
patients during treatment with indinavir. Because it is unknown whether indinavir will exacerbate 
physiologic hyperbilirubinaemia in neonates, careful consideration must be given to the use of 
indinavir in pregnant women at the time of delivery (see section 4.8).

In Rhesus monkeys, administration of indinavir to neonates caused a mild exacerbation of the 
transient physiologic hyperbilirubinaemia seen in this species after birth. Administration of indinavir 
to pregnant Rhesus monkeys during the third trimester did not cause a similar exacerbation in 
neonates; however, only limited placental transfer of indinavir occurred.

Breast-feeding
It is recommended that HIVinfected women do not breastfeed their infants under any 
circumstances in order to avoid transmission of HIV. It is not known whether indinavir is excreted in 
human milk. Mothers should be instructed to discontinue breastfeeding during treatment. 

Fertility
There are no data available regarding potential effects of CRIXIVAN treatment on male or female 
fertility.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. There are no 
data to suggest that indinavir affects the ability to drive and use machines. However, patients should 
be informed that dizziness and blurred vision have been reported during treatment with indinavir.

4.8 Undesirable effects

Nephrolithiasis occurred in approximately 10 % of patients treated with the recommended 
(unboosted) dose of CRIXIVAN in a pooled analysis of controlled clinical trials (see also below table 
and in section 4.4). 

Clinical adverse reactions reported by the investigators as possibly, probably, or definitely related to 
CRIXIVAN in  5 % of patients treated with CRIXIVAN monotherapy or in combination with 
NRTI(s) (n = 309) for 24 weeks are listed below. Many of these adverse reactions were also identified 
as common pre–existing or frequently occurring medical conditions in this population. These adverse 
reactions were: nausea (35.3 %), headache (25.2 %), diarrhoea (24.6 %), asthenia/fatigue (24.3 %), 
rash (19.1 %), taste perversion (19.1 %), dry skin (16.2 %), abdominal pain (14.6 %), vomiting 
(11.0 %), dizziness (10.7 %). With the exception of dry skin, rash, and taste perversion, the incidence 
of clinical adverse reactions was similar or higher among patients treated with antiretroviral 
nucleoside analogue controls than among patients treated with CRIXIVAN monotherapy or in 
combination with NRTI(s). This overall safety profile remained similar for 107 patients treated with 
CRIXIVAN monotherapy or in combination with NRTI(s) for up to 48 weeks. Adverse reactions, 
including nephrolithiasis, may lead to treatment interruption.

 



18

In controlled clinical trials conducted world–wide, indinavir was administered alone or in 
combination with other antiretroviral agents (zidovudine, didanosine, stavudine, and/or lamivudine) to 
approximately 2,000 patients, the majority of whom were adult Caucasian males (15 % females).

Indinavir did not alter the type, frequency, or severity of known major adverse effects associated with 
the use of zidovudine, didanosine, or lamivudine.

The following adverse reactions have been reported during clinical studies in adults and/or post-
marketing use for CRIXIVAN monotherapy and/or CRIXIVAN with combination antiretroviral 
therapy (CART).

Very common (≥ 1/10); Common (≥ 1/100 to  1/10); Uncommon (≥ 1/1,000 to < 1/100); 
Rare (≥ 1/10,000 to  1/1,000); Very rare (< 1/10,000); not known (cannot be estimated from the 
available data). Adverse reactions have also been reported during post-marketing experience* as they 
are derived from spontaneous reports, incidences cannot be determined.

System Organ Class Frequency Adverse reactions
CRIXIVAN

Blood and lymphatic system 
disorders

Very 
common

Not known*

increases in MCV, decreases in neutrophils 

increased spontaneous bleeding in patients with 
haemophilia, anemia including acute haemolytic 
anaemia, thrombocytopenia (see section 4.4).

Immune system disorders Not known* anaphylactoid reactions
Metabolism and nutrition 
disorders

Not known* new onset diabetes mellitus or hyperglycaemia, or 
exacerbation of pre-existing diabetes mellitus, 
hypertriglyceridaemia, hypercholesterolaemia.

Nervous system disorders Very 
common

Common

Not known*

headache, dizziness

insomnia, hypoaesthesia; paraesthesia

oral paraesthesia.
Gastrointestinal disorders Very 

common

Common

Not known*

nausea, vomiting, diarrhoea, dyspepsia

flatulence, dry mouth, acid regurgitation

hepatitis, including reports of hepatic failure, 
pancreatitis.

Hepato-biliary disorders Very 
Common

Not known*

isolated asymptomatic hyperbilirubinaemia, 
increased ALT and AST 

liver function abnormalities

 



19

System Organ Class Frequency Adverse reactions
CRIXIVAN

Skin and subcutaneous tissue 
disorders

Very 
common

Common

Not known*

rash, dry skin

pruritus

rash including erythema multiforme and Stevens 
Johnson syndrome, hypersensitivity vasculitis, 
alopecia, hyperpigmentation, urticaria; ingrown 
toenails and/or paronychia.

Musculoskeletal and connective 
tissue disorders

Common

Not known*

myalgia

myositis, rhabdomyolysis, increased CPK,
osteonecrosis (see section 4.4), periarthritis.

Renal and urinary disorders Very 
common

Common

Not known*

haematuria, proteinuria, crystalluria

nephrolithiasis, dysuria.

nephrolithiasis, in some cases with renal 
insufficiency or acute renal failure; pyelonephritis, 
interstitial nephritis, sometimes associated with 
indinavir crystal deposits. In some patients, 
resolution of the interstitial nephritis did not occur 
following discontinuation of indinavir therapy; 
renal insufficiency, renal failure, leucocyturia (see 
section 4.4).

General disorders and 
administration site conditions

Very 
common

asthenia/fatigue, taste perversion, abdominal pain.

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4).

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. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4).

Description of selected adverse reactions
Nephrolithiasis
Nephrolithiasis, including flank pain with or without haematuria (including microscopic haematuria), 
has been reported in approximately 10 % (252/2,577) of patients receiving CRIXIVAN in clinical 
trials at the recommended dose compared to 2.2 % in the control arms. In general, these events were 
not associated with renal dysfunction and resolved with hydration and temporary interruption of 
therapy (e.g., 1–3 days).

Hyperbilirubinaemia 
Isolated asymptomatic hyperbilirubinaemia (total bilirubin  2.5 mg/dL, 43 mcmol/L) was reported 
predominantly as elevated indirect bilirubin and rarely associated with elevations in ALT, AST, or 

 



20

alkaline phosphatase, has occurred in approximately 14 % of patients treated with CRIXIVAN alone 
or in combination with other antiretroviral agents. Most patients continued treatment with CRIXIVAN
without dose reduction and bilirubin values gradually declined toward baseline. Hyperbilirubinaemia 
occurred more frequently at doses exceeding 2.4 g/day compared to doses less than 2.4 g/day. 

Paediatric population
In clinical trials in paediatric patients (≥ 3 years), the adverse reaction profile was similar to that for 
adult patients except for a higher frequency of nephrolithiasis of 29 % (20/70) in paediatric patients 
treated with CRIXIVAN. Asymptomatic pyuria of unknown etiology was noted in 10.9 % (6/55) of 
paediatric patients who received CRIXIVAN. Some of these events were associated with mild 
elevation of serum creatinine.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

There have been reports of human overdose with CRIXIVAN. The most commonly reported 
symptoms were gastro-intestinal (e.g., nausea, vomiting, diarrhoea) and renal (e.g., nephrolithiasis, 
flank pain, haematuria).

It is not known whether indinavir is dialyzable by peritoneal or haemodialysis. 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitor, ATC code JO5AE02

Mechanism of action
Indinavir inhibits recombinant HIV–1 and HIV–2 protease with an approximate tenfold selectivity for 
HIV–1 over HIV–2 proteinase. Indinavir binds reversibly to the protease active site and inhibits 
competitively the enzyme, thereby preventing cleavage of the viral precursor polyproteins that occurs 
during maturation of the newly formed viral particle. The resulting immature particles are non–
infectious and are incapable of establishing new cycles of infection. Indinavir did not significantly 
inhibit the eukaryotic proteases human renin, human cathepsin D, human elastase, and human factor 
Xa.

Microbiology
Indinavir at concentrations of 50 to 100 nM mediated 95 % inhibition (IC95) of viral spread (relative 
to an untreated virus–infected control) in human T–lymphoid cell cultures and primary human 
monocytes/macrophages infected with HIV1 variants LAI, MN, RF, and a macrophage–tropic 
variant SF–162, respectively. Indinavir at concentrations of 25 to 100 nM mediated 95 % inhibition of 
viral spread in cultures of mitogen–activated human peripheral blood mononuclear cells infected with 
diverse, primary clinical isolates of HIV1, including isolates resistant to zidovudine and non–
nucleoside reverse transcriptase inhibitors (NNRTIs). Synergistic antiretroviral activity was observed 
when human T–lymphoid cells infected with the LAI variant of HIV–1 were incubated with indinavir 
and either zidovudine, didanosine, or NNRTIs.

Medicinal product resistance
Loss of suppression of viral RNA levels occurred in some patients; however, CD4 cell counts were 
often sustained above pre–treatment levels. When loss of viral RNA suppression occurred, it was 

 

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21

typically associated with replacement of circulating susceptible virus with resistant viral variants. 
Resistance was correlated with the accumulation of mutations in the viral genome that resulted in the 
expression of amino acid substitutions in the viral protease.

At least eleven amino acid sites in the protease have been associated with indinavir resistance: L10, 
K20, L24, M46, I54, L63, I64, A71, V82, I84, and L90. The basis for their contributions to resistance, 
however, is complex. None of these substitutions was either necessary or sufficient for resistance. For 
example, no single substitution or pair of substitutions was capable of engendering measurable 
( four–fold) resistance to indinavir, and the level of resistance was dependent on the ways in which 
multiple substitutions were combined. In general, however, higher levels of resistance resulted from 
the co–expression of greater numbers of substitutions at the eleven identified positions. Among 
patients experiencing viral RNA rebound during indinavir monotherapy at 800 mg q8h, substitutions 
at only three of these sites were observed in the majority of patients: V82 (to A or F), M46 (to I or L), 
and L10 (to I or R). Other substitutions were observed less frequently. The observed amino acid 
substitutions appeared to accumulate sequentially and in no consistent order, probably as a result of 
ongoing viral replication.

It should be noted that the decrease in suppression of viral RNA levels was seen more frequently 
when therapy with indinavir was initiated at doses lower than the recommended oral dose of 
2.4 g/day. Therefore, therapy with indinavir should be initiated at the recommended dose to 
increase suppression of viral replication and therefore inhibit the emergence of resistant virus.

The concomitant use of indinavir with nucleoside analogues (to which the patient is naive) may lessen 
the risk of the development of resistance to both indinavir and the nucleoside analogues. In one 
comparative trial, combination therapy with nucleoside analogues (triple therapy with zidovudine plus
didanosine) conferred protection against the selection of virus expressing at least one resistance–
associated amino acid substitution to both indinavir (from 13/24 to 2/20 at therapy week 24) and to 
the nucleoside analogues (from 10/16 to 0/20 at therapy week 24).

Cross resistance
HIV1 patient isolates with reduced susceptibility to indinavir expressed varying patterns and degrees 
of cross–resistance to a series of diverse HIV PIs, including ritonavir and saquinavir. Complete 
crossresistance was noted between indinavir and ritonavir; however, crossresistance to saquinavir 
varied among isolates. Many of the protease amino acid substitutions reported to be associated with 
resistance to ritonavir and saquinavir were also associated with resistance to indinavir.

Pharmacodynamic effects 

Adults
Treatment with indinavir alone or in combination with other antiretroviral agents (i.e., nucleoside 
analogues) has so far been documented to reduce viral load and increase CD4 lymphocytes in patients 
with CD4 cell counts below 500 cells/mm3.

In one published study, 20 HIV-infected patients with undetectable plasma viral load 
(< 200 copies/mL) receiving indinavir 800 mg every 8 hours were switched in an open, cross-over 
design to indinavir/ritonavir 400/100 mg every 12 hours. Eighteen patients completed the study to 
week 48. Viral load remained < 200 copies/mL for 48 weeks in all patients. 

Another published study evaluated the efficacy and safety of indinavir/ritonavir 400/100 mg every 
12 hours in 40 antiretroviral-naïve patients. Thirty subjects completed 48 weeks of treatment. At 
week 4, the indinavir Cmin was 500 ng/mL with substantial trough variability (range 5 to 
8,100 ng/mL). By intent to treat analysis 65 % of patients had HIV RNA < 400 copies/mL and 50 % 
had viral load < 50 copies/mL; by on-treatment analysis 96 % of patients had HIV RNA 
< 400 copies/mL and 74 % had viral load < 50 copies/mL.

 



22

Eighty antiretroviral naïve patients were entered into a third published study. In this open label non-
randomized single arm study, patients were treated with stavudine and lamivudine plus 
indinavir/ritonavir 400/100 mg every 12 hours. Sixty-two patients completed the study to week 96. In 
the intent to treat and on treatment analyses the proportion of patients with HIV RNA of 
< 50 copies/mL was 68.8 % and 88.7 %, respectively, at week 96.

Indinavir alone or in combination with nucleoside analogues (zidovudine/stavudine and lamivudine) 
has been shown to delay clinical progression rate compared with nucleoside analogues and to provide 
a sustained effect on viral load and CD4 count.

In zidovudine experienced patients, indinavir, zidovudine and lamivudine in combination compared 
with lamivudine added to zidovudine reduced the probability of AIDS defining illness or death 
(ADID) at 48 weeks from 13 % to 7 %. Similarly, in antiretroviral naive patients, indinavir with and 
without zidovudine compared with zidovudine alone reduced the probability of ADID at 48 weeks 
from 15 % with zidovudine alone to approximately 6 % with indinavir alone or in combination with 
zidovudine.

Effects on viral load were consistently more pronounced in patients treated with indinavir in 
combination with nucleoside analogues, but the proportion of patients with serum viral RNA below 
the limit of quantification (500 copies/mL) varied between studies, at week 24 from 40 % to more 
than 80 %. This proportion tends to remain stable over prolonged periods of follow–up. Similarly, 
effects on CD4 cell count tend to be more pronounced in patients treated with indinavir in 
combination with nucleoside analogues compared with indinavir alone. Within studies, this effect is 
sustained also after prolonged periods of follow–up.

Paediatric population
Two clinical trials in 41 paediatric patients (4 to 15 years of age) were designed to characterise the 
safety, antiretroviral activity, and pharmacokinetics of indinavir in combination with stavudine and 
lamivudine. In one study, at week 24, the proportion of patients with plasma viral RNA below 
400 copies/mL was 60 %; the mean increase in CD4 cell counts was 242 cells/mm3; and the mean 
increase in percent CD4 cell counts was 4.2 %. At week 60, the proportion of patients with plasma 
viral RNA below 400 copies/mL was 59 %. In another study, at week 16, the proportion of patients 
with plasma viral RNA below 400 copies/mL was 59 %; the mean increase in CD4 cell counts was 
73 cells/mm3; and the mean increase in percent CD4 cell counts was 1.2 %. At week 24, the 
proportion of patients with plasma viral RNA below 400 copies/mL was 60 %.

5.2 Pharmacokinetic properties

Absorption
Indinavir is rapidly absorbed in the fasted state with a time to peak plasma concentration of 0.8 hours 
± 0.3 hours (mean ± S.D.). A greater than dose–proportional increase in indinavir plasma 
concentrations was observed over the 200 – 800 mg dose range. Between 800–mg and 1,000–mg dose 
levels, the deviation from dose–proportionality is less pronounced. As a result of the short half–life, 
1.8 ± 0.4 hours, only a minimal increase in plasma concentrations occurred after multiple dosing. The 
bioavailability of a single 800–mg dose of indinavir was approximately 65 % (90 % CI, 58 – 72 %).

Data from a steady state study in healthy volunteers indicate that there is a diurnal variation in the 
pharmacokinetics of indinavir. Following a dose regimen of 800 mg every 8 hours, measured peak 
plasma concentrations (Cmax) after morning, afternoon and evening doses were 15,550 nM, 8,720 nM 
and 8,880 nM, respectively. Corresponding plasma concentrations at 8 hours post dose were 220 nM, 
210 nM and 370 nM, respectively. The relevance of these findings for ritonavir boosted indinavir is 
unknown. At steady state following a dose regimen of 800 mg every 8 hours, HIV–seropositive adult 
patients in one study achieved geometric means of: AUC0-8h of 27,813 nM*h (90 % confidence 
interval = 22,185, 34,869), peak plasma concentrations 11,144 nM (90 % confidence interval = 9,192, 
13,512) and plasma concentrations at 8 hours post dose 211 nM (90 % confidence interval = 163, 
274).

 



23

Food effect
At steady state following a dose regimen of 800 mg/100 mg of indinavir/ritonavir every 12 hours with 
a low-fat meal, healthy volunteers in one study achieved geometric means: AUC0-12h 116,067 nM*h 
(90 % confidence interval = 101,680, 132,490), peak plasma concentrations 19,001 nM (90 % 
confidence interval = 17,538, 20,588), and plasma concentrations at 12 hours post dose 2,274 nM 
(90 % confidence interval = 1,701, 3,042). No significant difference in exposure was seen when the 
regimen was given with a high-fat meal. 

Indinavir boosted regimen. Limited data are available on the pharmacokinetics of indinavir in 
association with low dose ritonavir. The pharmacokinetics of indinavir (400 mg) with ritonavir 
(100 mg) dosed twice daily was examined in two studies. Pharmacokinetic analysis in one study was 
performed on nineteen of the patients, with a median (range) indinavir AUC 0-12hr, Cmax, and Cmin 
of 25,421 nM*h (21,489 – 36,236 nM*h), 5,758 nM (5,056 – 6,742 nM) and 239 (169 – 421 nM), 
respectively. The pharmacokinetic parameters in the second study were comparable.

In HIVinfected paediatric patients, a dose regimen of indinavir hard capsules, 500 mg/m2 every 
8 hours, produced AUC0–8hr values of 27,412 nM*h, peak plasma concentrations of 12,182 nM, and 
plasma concentrations at 8 hours post dose of 122 nM. The AUC and peak plasma concentrations 
were generally similar to those previously observed in HIV–infected adults receiving the 
recommended dose of 800 mg every 8 hours; it should be observed that the plasma concentrations 
8 hours post dose were lower.

During pregnancy, it has been demonstrated that the systemic exposure of indinavir is relevantly 
decreased (PACTG 358. Crixivan, 800 mg every 8 hours + zidovudine 200 mg every 8 hours and 
lamivudine 150 mg twice a day). The mean indinavir plasma AUC0-8hr at week 30-32 of gestation 
(n = 11) was 9,231 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 section 4.6). 

Administration of indinavir with a meal high in calories, fat, and protein resulted in a blunted and 
reduced absorption with an approximate 80 % reduction in AUC and an 86 % reduction in Cmax. 
Administration with light meals (e.g., dry toast with jam or fruit conserve, apple juice, and coffee with 
skimmed or fat–free milk and sugar or corn flakes, skimmed or fat–free milk and sugar) resulted in 
plasma concentrations comparable to the corresponding fasted values.

The pharmacokinetics of indinavir taken as indinavir sulphate salt (from opened hard capsules) mixed 
in apple sauce were generally comparable to the pharmacokinetics of indinavir taken as hard capsules, 
under fasting conditions. In HIV–infected paediatric patients, the pharmacokinetic parameters of 
indinavir in apple sauce were: AUC0–8hr of 26,980 nM*h; peak plasma concentration of 13,711 nM; 
and plasma concentration at 8 hours post dose of 146 nM.

Distribution
Indinavir was not highly bound to human plasma proteins (39 % unbound). 

There are no data concerning the penetration of indinavir into the central nervous system in humans.

Biotransformation
Seven major metabolites were identified and the metabolic pathways were identified as 
glucuronidation at the pyridine nitrogen, pyridine–N–oxidation with and without 3’–hydroxylation on 
the indane ring, 3’–hydroxylation of indane, p–hydroxylation of phenylmethyl moiety, and 
N-depyridomethylation with and without the 3’–hydroxylation. In vitro studies with human liver 
microsomes indicated that CYP3A4 is the only P450 isozyme that plays a major role in the oxidative 

 



24

metabolism of indinavir. Analysis of plasma and urine samples from subjects who received indinavir 
indicated that indinavir metabolites had little proteinase inhibitory activity.

Elimination
Over the 200–1,000–mg dose range administered in both volunteers and HIV infected patients, there 
was a slightly greater than dose–proportional increase in urinary recovery of indinavir. Renal 
clearance (116 mL/min) of indinavir is concentration–independent over the clinical dose range. Less 
than 20 % of indinavir is excreted renally. Mean urinary excretion of unchanged medicinal product 
following single dose administration in the fasted state was 10.4 % following a 700–mg dose, and 
12.0 % following a 1,000–mg dose. Indinavir was rapidly eliminated with a half–life of 1.8 hours.

Characteristics in patients
Pharmacokinetics of indinavir do not appear to be affected by race.

There are no clinically significant differences in the pharmacokinetics of indinavir in HIV 
seropositive women compared to HIV seropositive men. 

Patients with mild–to–moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence 
of decreased metabolism of indinavir resulting in approximately 60 % higher mean AUC following a
400–mg dose. The mean half–life of indinavir increased to approximately 2.8 hours.

5.3 Preclinical safety data

Crystals have been seen in the urine of rats, one monkey, and one dog. The crystals have not been 
associated with medicinal product –induced renal injury. An increase in thyroidal weight and 
thyroidal follicular cell hyperplasia, due to an increase in thyroxine clearance, was seen in rats treated 
with indinavir at doses  160 mg/kg/day. An increase in hepatic weight occurred in rats treated with
indinavir at doses  40 mg/kg/day and was accompanied by hepatocellular hypertrophy at doses 
 320 mg/kg/day. 

The maximum non–lethal oral dose of indinavir was at least 5,000 mg/kg in rats and mice, the highest 
dose tested in acute toxicity studies.

Studies in rats indicated that uptake into brain tissue was limited, distribution into and out of the 
lymphatic system was rapid, and excretion into the milk of lactating rats was extensive. Distribution 
of indinavir across the placental barrier was significant in rats, but limited in rabbits.

Mutagenicity
Indinavir did not have any mutagenic or genotoxic activity in studies with or without metabolic 
activation.

Carcinogenicity
No carcinogenicity was noted in mice at the maximum tolerated dose, which corresponded to a 
systemic exposure approximately 2 to 3 times higher than the clinical exposure. In rats, at similar 
exposure levels, an increased incidence of thyroid adenomas was seen, probably related to an increase 
in release of thyroid stimulating hormone secondary to an increase in thyroxine clearance. The 
relevance of the findings to humans is likely limited.

Developmental Toxicity
Developmental toxicity studies were performed in rats, rabbits and dogs (at doses which produced 
systemic exposures comparable to or slightly greater than human exposure) and revealed no evidence 
of teratogenicity. No external or visceral changes were observed in rats, however, increases in the 
incidence of supernumerary ribs and of cervical ribs were seen. No external, visceral, or skeletal 
changes were observed in rabbits or dogs. In rats and rabbits, no effects on embryonic/foetal survival 
or foetal weights were observed. In dogs, a slight increase in resorptions was seen; however, all 

 



25

foetuses in medication–treated animals were viable, and the incidence of live foetuses in medication–
treated animals was comparable to that in controls.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
anhydrous lactose 
magnesium stearate

Capsule shell:
gelatin
titanium dioxide (E 171)
printing ink: indigo carmine (E 132).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years 

6.4 Special precautions for storage

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.

6.5 Nature and contents of container

HDPE bottle with a polypropylene cap and a foil induction cap containing 180, 270 or 360 capsules. 

Not all pack sizes may be marketed. 

6.6 Special precautions for disposal and other handling

The bottles contain desiccant canisters that should remain in the container. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/96/024/001
EU/1/96/024/002
EU/1/96/024/003

 



26

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 04 October 1996
Date of latest renewal: 18 July 2011

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 



27

1. NAME OF THE MEDICINAL PRODUCT

CRIXIVAN 400 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect
Each 400 mg capsule contains 149.6 mg of lactose.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Hard capsule.

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.

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
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).

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).

 



28

Paediatric population 
The safety and efficacy of CRIXIVAN in children under the age of 4 years have not been established 
(see sections 5.1 and 5.2). Currently available data in children above the age of 4 years are described 
in sections 4.8, 5.1, and 5.2.

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 co-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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 should not be administered concurrently with amiodarone, 
terfenadine, cisapride, astemizole, quetiapine, 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 must not be administered with alfuzosin, meperidine, piroxicam, 
propoxyphene, bepridil, encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine, 
clorazepate, diazepam, estazolam and flurazepam.

Indinavir must not be given with ritonavir to patients with decompensated liver disease as ritonavir is 
principally metabolized 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 patients with a cumulative frequency of 
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 over time remains 
relatively constant. 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 

 



29

(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. 
Evaluation may consist of urinalysis, serum BUN and creatinine, and ultrasound of the bladder and 
kidneys. Adequate hydration is recommended in all patients on indinavir (see sections 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, 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).

HIV Transmission
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent 
transmission should be taken in accordance with national guidelines.

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.

Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

 



30

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.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment.

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. 

 



31

4.5 Interaction with other medicinal products and other forms of interaction

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, quetiapine, 
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 “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”, once daily as 
“QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").

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.

 



32

Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

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 1,000 mg TID)

Indinavir AUC: 
Indinavir Cmin: 
(Relative to Indinavir 1,000 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 1,000 mg TID)

Efavirenz 200 mg QD
(Indinavir 800 mg TID)

Indinavir AUC:  46 %
Indinavir Cmin:  57 %
(Relative to Indinavir 800 mg TID alone)

An increased dose (1,000 mg TID) of indinavir 
does not compensate for the inducing effect of 
efavirenz.

Indinavir AUC:  31 %
Indinavir Cmin:  40 %

Efavirenz AUC: 

No specific dose 
recommendation can be 
given.

Nevirapine 200 mg BID
(Indinavir 800 mg TID)

Indinavir AUC:  28 %
Nevirapine:  (CYP3A induction)

A dose increase of indinavir 
to 1,000 mg every 8 hours 
should be considered if 
given with nevirapine.

PIs
Amprenavir 1,200 mg BID
(Indinavir 1,200 mg BID)

Amprenavir AUC: ↑ 90 %
Indinavir: ↔ 

The appropriate doses for 
this combination, with 
respect to efficacy and 
safety, have not been 
established.

 



33

Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

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 1,200 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 1,200 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. 

 



34

Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

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 1,000 mg TID)

Indinavir AUC: ↓ 24 % 
Indinavir Cmin: 
(Relative to Indinavir 1,000 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: ↓ 20 %
Indinavir Cmin: ↑ 29 %
(Relative to Indinavir 800 mg TID alone)
Indinavir AUC ↓ 56 %
Indinavir Cmin ↓ 27 %
(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 ↓ 34 %
Indinavir Cmin : ↓ 39 %
(Relative to Indinavir 800 mg TID alone)

Rifabutin AUC: ↑ 173 %
Rifabutin Cmin: ↑ 244 %
(Relative to rifabutin 300 mg QD alone)

Indinavir AUC: ↓ 32 %
Indinavir Cmin: ↓ 40 %
(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:  92 %
(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.

 



35

Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

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 
coadministered 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:  28 %
(Relative to Indinavir 800 mg SD alone)
Venlafaxine and active metabolite O-
desmethyl-venlafaxine: 

The clinical significance of 
this finding is unknown.

ANTIPSYCHOTICS
Quetiapine Not studied. Due to CYP3A inhibition by 

indinavir, concentrations
of quetiapine are expected to
increase.

Concomitant administration 
of indinavir and quetiapine 
may increase plasma 
concentrations of quetiapine 
leading to quetiapine-related 
toxicity, including coma. 
Co-administration of 
quetiapine with indinavir is 
contraindicated (see 
section 4.3).

CALCIUM CHANNEL 
BLOCKERS
Dihydropyridine: e.g., 
felodipine, nifedipine, 
nicardipine

 dihydropyridine calcium channel blocker 
concentration

Calcium channel blockers are metabolized by 
CYP3A4 which is inhibited by indinavir.

Caution is warranted and 
clinical monitoring of 
patients is recommended.

 



36

Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

HERBAL MEDICATIONS
St. John’s wort (Hypericum 
perforatum) 300 mg TID
(Indinavir 800 mg TID)

Indinavir AUC:  54 %
Indinavir Cmin: ↓ 81 %
(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 INHIBITORS
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)

Combination not 
recommended

Atorvastatin  atorvastatin concentration
Atorvastatin is less dependent on CYP3A4 for 
metabolism than lovastatin or simvastatin

Use the lowest possible 
dose of atorvastatin with 
careful monitoring. Caution 
is advised.

Pravastatin, fluvastatin Interaction not studied
Metabolism of pravastatin and fluvastatin is not 
dependent on CYP3A4. Interaction via effects 
on transport proteins cannot be excluded.

Interaction unknown. If no 
alternative treatment is 
available, use with careful 
monitoring.

IMMUNOSUPPRESSIVES
Cyclosporine A Cyclosporine A (CsA) levels markedly increase 

in patients on PIs, including indinavir.
CsA levels require 
progressive dose adjustment 
using therapeutic medicinal 
product monitoring.

ORAL CONTRACEPTIVES
Norethindrone/ethinyl estradiol
1/35 1 mcg QD
(Indinavir 800 mg TID)

Norethindrone AUC: ↑ 26 %
Norethindrone Cmin: ↑ 44 %

Indinavir and 
norethindrone/ethinyl 
estradiol 1/35 can be co-
administered without dose 
adjustment.

 



37

Medicinal products by 
therapeutic areas

Interaction Recommendations 
concerning co-
administration

PDE5 INHIBITOR
Sildenafil 25 mg SD
(Indinavir 800 mg TID)

Indinavir AUC:  11 %
Sildenafil AUC  340 %

Coadministration of CRIXIVAN with sildenafil 
is likely to result in an increase of sildenafil by 
competitive inhibition of metabolism.

Sildenafil dose should not 
exceed a maximum of 
25 mg in a 48-hour period 
in patients receiving 
concomitant indinavir 
therapy.

Vardenafil 10 mg SD
(Indinavir 800 mg TID)

Vardenafil AUC: ↑ 16-fold

Coadministration of CRIXIVAN with 
vardenafil is likely to result in an increase of 
vardenafil by competitive inhibition of 
metabolism.

Vardenafil dose should not 
exceed a maximum of 
2.5 mg in a 24-hour period 
in patients receiving 
concomitant indinavir 
therapy.

Tadalafil Interaction not studied

Coadministration of CRIXIVAN with tadalafil 
is likely to result in an increase of tadalafil by 
competitive inhibition of metabolism.

Tadalafil dose should not 
exceed a maximum of 
10 mg in a 72 hour period in 
patients receiving 
concomitant indinavir 
therapy.

SEDATIVES/HYPNOTICS
Midazolam (parenteral) Not studied, combined administrations are 

expected to significantly increase 
concentrations of midazolam, particularly when 
midazolam is given orally.

Midazolam is extensively metabolized by 
CYP3A4.

CRIXIVAN and oral 
midazolam should not be 
coadministered (see 
section 4.3). Caution should 
be used with 
coadministration of 
CRIXIVAN and parenteral 
midazolam. If CRIXIVAN 
is coadministered with 
parenteral midazolam, it 
should be done in an 
intensive care unit with 
close clinical monitoring in 
case of respiratory 
depression and/or prolonged 
sedation. Dose adjustment 
for midazolam should be 
considered, especially if 
more than a single dose of 
midazolam is administered.

STEROIDS
Dexamethasone Interaction not studied

 dexamethasone exposure expected (CYP3A 
inhibition).  
 indinavir plasma concentrations may be 
expected (CYP3A induction).

Careful monitoring of 
therapeutic and adverse 
effects is recommended 
when dexamethasone is 
concomitantly administered 
with indinavir.

 



38

Table 2. Interactions and dose recommendations with other medical products – INDINAVIR 
BOOSTED WITH RITONAVIR. No specific interaction studies have been performed with the 
boosted dose 400 mg indinavir with 100 mg ritonavir.

Interactions between indinavir/ritonavir and other medicinal products are listed in the tables below 
(increase is indicated as “↑”, decrease as “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”, 
once daily as “QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").

Medicinal products by 
therapeutic areas

Interaction Recommendations concerning 
co-administration

ANTI-INFECTIVES
Antiretrovirals
Amprenavir Amprenavir 1,200 mg BID AUC ↑90 % with 

800 mg TID indinavir alone (see Table 1).  
Amprenavir 600 mg BID AUC ↑ 64 % with 
100 mg BID ritonavir alone (relative to 
amprenavir 1,200 mg BID alone). Ritonavir 
increases the serum levels of amprenavir as a 
result of CYP3A4 inhibition.
There are no interaction data available on the 
coadministration of indinavir/ritonavir and 
amprenavir. 

The appropriate doses for this 
combination, with respect to 
efficacy and safety, have not 
been established.  Ritonavir
oral solution should not be co-
administered with amprenavir 
oral solution to children due to 
the risk of toxicity from 
excipients in the two 
formulations.

Efavirenz 600 mg QD
(Indinavir/ritonavir 800/100 
BID)

Indinavir AUC: 25 %
Indinavir Cmin ↓ 50 %
(Relative to Indinavir/ritonavir 800/100 BID 
alone)

Ritonavir AUC ↓ 36 %
Ritonavir Cmin: 39 %

Efavirenz AUC and Cmin : ↔

Dose increases of 
indinavir/ritonavir when given 
in combination with efavirenz 
have not been studied.

Anti-Mycobacterial
Rifabutin Interaction with indinavir/ritonavir not studied 

Decreased indinavir concentrations and 
increased rifabutin concentrations are 
expected.

No dose recommendations for 
indinavir/ritonavir with 
rifabutin could be given, 
therefore the combination is 
not recommended.  If rifabutin 
treatment is required, 
alternative agents for treating 
HIV infection should be 
sought.

Rifampicin Rifampicin is a strong CYP3A4 inducer and
has been shown to cause a 92 % decrease in 
indinavir AUC which 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.

The combination of rifampicin 
and CRIXIVAN with 
concomitant low-dose ritonavir
is contraindicated (see 
section 4.3).

Other Anti-infectives
Atovaquone Interaction with indinavir/ritonavir not studied 

Ritonavir induces glucuronidation and as a 
result is expected to decrease the plasma 
concentrations of atovaquone.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
atovaquone is concomitantly 
administered with 
indinavir/ritonavir.

 



39

Medicinal products by 
therapeutic areas

Interaction Recommendations concerning 
co-administration

Erythromycin, Itraconazole Interaction with indinavir/ritonavir not studied 
Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of erythromycin and 
itraconazole.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
erythromycin or itraconazole 
are concomitantly 
administered with 
indinavir/ritonavir.

Ketoconazole Interaction with indinavir/ritonavir not studied  
Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of ketoconazole. Co-
administration of ritonavir and ketoconazole 
caused an increased incidence of 
gastrointestinal and hepatic adverse events.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
ketoconazole is concomitantly 
administered with 
indinavir/ritonavir. A dose 
reduction of ketoconazole 
should be considered when co-
administered with 
indinavir/ritonavir.

ANALGESICS
Fentanyl Interaction with indinavir/ritonavir not studied 

Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of fentanyl.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when fentanyl 
is concomitantly administered 
with indinavir/ritonavir.

Methadone Interaction with indinavir/ritonavir not studied

There is no significant effect of unboosted 
indinavir on methadone AUC (see Table 1 
above).

Decreases in methadone AUC has been 
observed with other ritonavir-boosted protease 
inhibitors.
Ritonavir may induce glucuronidation of 
methadone.

Increased methadone dose may 
be necessary when 
concomitantly administered 
with indinavir/ritonavir. Dose 
adjustment should be 
considered based on the 
patient’s clinical response to 
methadone therapy.

Morphine Interaction with indinavir/ritonavir not studied 
Morphine levels may be decreased due to 
induction of glucuronidation by 
coadministered ritonavir.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
morphine is concomitantly 
administered with 
indinavir/ritonavir.

ANTIARRTHYMICS
Digoxin 0.4 mg SD
Ritonavir 200 mg BID

Interaction with indinavir/ritonavir not studied 
Digoxin AUC:  22 %

Ritonavir may increase 
digoxin levels due to 
modification of P-glycoprotein 
mediated digoxin efflux. 
Careful monitoring of digoxin 
levels is recommended when 
digoxin is concomitantly 
administered with 
indinavir/ritonavir.

ANTICOAGULANT
Warfarin
Ritonavir 400 mg BID

Interaction with indinavir/ritonavir not studied
R-warfarin levels may be decreased leading to 
reduced anticoagulation due to induction of 
CYP1A2 and CYP2C9 by ritonavir.

Anticoagulation parameters 
should be monitored when 
warfarin is coadministered 
with indinavir/ritonavir.

 



40

Medicinal products by 
therapeutic areas

Interaction Recommendations concerning 
co-administration

ANTICONVULSANTS
Carbamazepine Interaction with indinavir/ritonavir not studied 

Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of carbamazepine.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
carbamazepine is 
concomitantly administered 
with indinavir/ritonavir.

Divalproex, lamotrigine, 
phenytoin

Interaction with indinavir/ritonavir not studied 
Ritonavir induces oxidation by CYP2C9 and 
glucuronidation and as a result is expected to 
decrease the plasma concentrations of 
anticonvulsants.

Careful monitoring of serum 
levels or therapeutic effects is 
recommended when these 
medicines are concomitantly 
administered with 
indinavir/ritonavir. Phenytoin 
may decrease serum levels of 
ritonavir.

ANTIDEPRESSANTS
Trazodone 50 mg SD
Ritonavir 200 mg BID

Interaction with indinavir/ritonavir not studied 
Trazodone AUC:  2.4-fold
An increase in the incidence in trazodone-
related adverse events was noted when 
coadministered with ritonavir.

The combination of trazodone 
with indinavir/ritonavir should 
be used with caution, initiating 
trazodone at the lowest dose 
and monitoring for clinical 
response and tolerability.

ANTIHISTAMINES
Fexofenadine Interaction with indinavir/ritonavir not studied 

Ritonavir may modify P-glycoprotein 
mediated fexofenadine efflux when 
coadministered resulting in increased 
concentrations of fexofenadine. 

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
fexofenadine is concomitantly 
administered with 
indinavir/ritonavir.

Loratidine Interaction with indinavir/ritonavir not studied 
Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of loratidine.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
loratidine is concomitantly 
administered with 
indinavir/ritonavir.

CALCIUM CHANNEL BLOCKERS
Diltiazem 120 mg QD
(Indinavir/ritonavir 800/100 
BID)

Diltiazem AUC0-24hr:  43 %
Indinavir/ritonavir AUCs: 

Dose modification of calcium 
channel blockers should be 
considered when co-
administered with 
indinavir/ritonavir as it may
result in an increased response.

Amlodipine 5 mg QD
(Indinavir/ritonavir 800/100 
BID)

Amlodipine AUC0-24hr:  80 %
Indinavir/ritonavir AUCs: 

HMG-CoA REDUCTASE INHIBITORS  Same recommendations as for 
indinavir without ritonavir 
boosting (see Table 1).

IMMUNOSUPPRESSIVES
Cyclosporine A
(Indinavir/ritonavir 800/100 
BID)

Following initiation of indinavir/ritonavir 
800/100 BID or lopinavir/ritonavir 400/100 
BID, dose reduction of cyclosporine A to 
5-20 % of prior dose was needed to maintain 
cyclosporine A levels within therapeutic range 
in one study.

Cyclosporine A dose 
adjustments should be made 
according to measured 
cyclosporine A trough blood 
levels.

Tacrolimus Interaction with indinavir/ritonavir not studied 
Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of tacrolimus.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
tacrolimus is concomitantly 
administered with 
indinavir/ritonavir.

 



41

Medicinal products by 
therapeutic areas

Interaction Recommendations concerning 
co-administration

PDE5 INHIBITOR
Sildenafil, tadalafil Interaction not studied.  For sildenafil and tadalafil, 

same recommendations as for 
indinavir without ritonavir 
boosting (see Table 1).

Vardenafil Interaction not studied. Vardenafil dose should not 
exceed a maximum of 2.5 mg 
in a 72-hour period when 
given with a boosted protease 
inhibitor.

SEDATIVES/HYPNOTICS
Buspirone Interaction with indinavir/ritonavir not studied 

Indinavir and ritonavir inhibit CYP3A4 and as 
a result are expected to increase the plasma 
concentrations of buspirone.

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
buspirone is concomitantly 
administered with 
indinavir/ritonavir.

Midazolam (parenteral) Interaction with indinavir/ritonavir 
Not studied, combined administrations are 
expected to significantly increase 
concentrations of midazolam, particularly 
when midazolam is given orally (CYP3A4 
inhibition).

CRIXIVAN with ritonavir and 
oral midazolam should not be 
coadministered (see 
section 4.3). Caution should be 
used with coadministration of 
CRIXIVAN with ritonavir and 
parenteral midazolam. If 
CRIXIVAN with ritonavir is 
coadministered with parenteral 
midazolam, it should be done 
in an intensive care unit with 
close clinical monitoring in 
case of respiratory depression 
and/or prolonged sedation. 
Dose adjustment for 
midazolam should be 
considered, especially if more 
than a single dose of 
midazolam is administered.

STEROIDS
Dexamethasone Interaction with indinavir/ritonavir not studied 

 dexamethasone exposure expected (CYP3A 
inhibition). 
 indinavir plasma concentrations may be 
expected (CYP3A induction).

Careful monitoring of 
therapeutic and adverse effects 
is recommended when 
dexamethasone is 
concomitantly administered 
with indinavir/ritonavir.

For information regarding diet or the effect of food on indinavir absorption (see sections 4.2 and 5.2).

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no adequate and well-controlled studies in pregnant patients. Indinavir should be used 
during pregnancy only if the potential benefit justifies the potential risk to the foetus. Given that 
substantially lower antepartum exposures have been observed in a small study of HIV-infected 
pregnant patients and the limited data in this patient population, indinavir use is not recommended in 
HIV-infected pregnant patients (see section 5.2). 

Hyperbilirubinaemia, reported predominantly as elevated indirect bilirubin, has occurred in 14 % of 
patients during treatment with indinavir. Because it is unknown whether indinavir will exacerbate 

 



42

physiologic hyperbilirubinaemia in neonates, careful consideration must be given to the use of 
indinavir in pregnant women at the time of delivery (see section 4.8).

In Rhesus monkeys, administration of indinavir to neonates caused a mild exacerbation of the 
transient physiologic hyperbilirubinaemia seen in this species after birth. Administration of indinavir 
to pregnant Rhesus monkeys during the third trimester did not cause a similar exacerbation in 
neonates; however, only limited placental transfer of indinavir occurred.

Breast-feeding
It is recommended that HIVinfected women do not breastfeed their infants under any 
circumstances in order to avoid transmission of HIV. It is not known whether indinavir is excreted in 
human milk. Mothers should be instructed to discontinue breastfeeding during treatment. 

Fertility
There are no data available regarding potential effects of CRIXIVAN treatment on male or female 
fertility.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. There are no 
data to suggest that indinavir affects the ability to drive and use machines. However, patients should 
be informed that dizziness and blurred vision have been reported during treatment with indinavir.

4.8 Undesirable effects

Nephrolithiasis occurred in approximately 10 % of patients treated with the recommended 
(unboosted) dose of CRIXIVAN in a pooled analysis of controlled clinical trials (see also below table 
and in section 4.4). 

Clinical adverse reactions reported by the investigators as possibly, probably, or definitely related to 
CRIXIVAN in  5 % of patients treated with CRIXIVAN monotherapy or in combination with 
NRTI(s) (n = 309) for 24 weeks are listed below. Many of these adverse reactions were also identified 
as common pre–existing or frequently occurring medical conditions in this population. These adverse 
reactions were: nausea (35.3 %), headache (25.2 %), diarrhoea (24.6 %), asthenia/fatigue (24.3 %), 
rash (19.1 %), taste perversion (19.1 %), dry skin (16.2 %), abdominal pain (14.6 %), vomiting 
(11.0 %), dizziness (10.7 %). With the exception of dry skin, rash, and taste perversion, the incidence 
of clinical adverse reactions was similar or higher among patients treated with antiretroviral 
nucleoside analogue controls than among patients treated with CRIXIVAN monotherapy or in 
combination with NRTI(s). This overall safety profile remained similar for 107 patients treated with 
CRIXIVAN monotherapy or in combination with NRTI(s) for up to 48 weeks. Adverse reactions, 
including nephrolithiasis, may lead to treatment interruption.

In controlled clinical trials conducted world–wide, indinavir was administered alone or in 
combination with other antiretroviral agents (zidovudine, didanosine, stavudine, and/or lamivudine) to 
approximately 2,000 patients, the majority of whom were adult Caucasian males (15 % females).

Indinavir did not alter the type, frequency, or severity of known major adverse reactions associated 
with the use of zidovudine, didanosine, or lamivudine.

The following adverse reactions have been reported during clinical studies in adults and/or post-
marketing use for CRIXIVAN monotherapy and/or CRIXIVAN with combination antiretroviral 
therapy (CART).

Very common (≥ 1/10); Common (≥ 1/100 to  1/10); Uncommon (≥ 1/1,000 to < 1/100); 
Rare (≥ 1/10,000 to  1/1,000); Very rare (< 1/10,000); not known (cannot be estimated from the 

 



43

available data). Adverse reactions have also been reported during post-marketing experience* as they 
are derived from spontaneous reports, incidences cannot be determined.

System Organ Class Frequency Adverse reactions
CRIXIVAN

Blood and lymphatic system 
disorders

Very 
common

Not known*

increases in MCV, decreases in neutrophils 

increased spontaneous bleeding in patients with 
haemophilia, anemia including acute haemolytic 
anaemia, thrombocytopenia (see section 4.4).

Immune system disorders Not known* anaphylactoid reactions
Metabolism and nutrition 
disorders

Not known* new onset diabetes mellitus or hyperglycaemia, or 
exacerbation of pre-existing diabetes mellitus, 
hypertriglyceridaemia, hypercholesterolaemia.

Nervous system disorders Very 
common

Common

Not known*

headache, dizziness

insomnia, hypoaesthesia; paraesthesia

oral paraesthesia.
Gastrointestinal disorders Very 

common

Common

Not known*

nausea, vomiting, diarrhoea, dyspepsia

flatulence, dry mouth, acid regurgitation

hepatitis, including reports of hepatic failure, 
pancreatitis.

Hepato-biliary disorders Very 
Common

Not known*

isolated asymptomatic hyperbilirubinaemia, 
increased ALT and AST 

liver function abnormalities
Skin and subcutaneous tissue 
disorders

Very 
common

Common

Not known*

rash, dry skin

pruritus

rash including erythema multiforme and Stevens 
Johnson syndrome, hypersensitivity vasculitis, 
alopecia, hyperpigmentation, urticaria; ingrown 
toenails and/or paronychia.

Musculoskeletal and connective 
tissue disorders

Common

Not known*

myalgia

myositis, rhabdomyolysis, increased CPK,
osteonecrosis (see section 4.4), periarthritis.

 



44

System Organ Class Frequency Adverse reactions
CRIXIVAN

Renal and urinary disorders Very 
common

Common

Not known*

haematuria, proteinuria, crystalluria

nephrolithiasis, dysuria.

nephrolithiasis, in some cases with renal 
insufficiency or acute renal failure; pyelonephritis, 
interstitial nephritis, sometimes associated with 
indinavir crystal deposits. In some patients, 
resolution of the interstitial nephritis did not occur 
following discontinuation of indinavir therapy; 
renal insufficiency, renal failure, leucocyturia (see 
section 4.4).

General disorders and 
administration site conditions

Very 
common

asthenia/fatigue, taste perversion, abdominal pain.

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4).

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. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (see section 4.4).

Description of selected adverse reactions
Nephrolithiasis
Nephrolithiasis, including flank pain with or without haematuria (including microscopic haematuria), 
has been reported in approximately 10 % (252/2,577) of patients receiving CRIXIVAN in clinical 
trials at the recommended dose compared to 2.2 % in the control arms. In general, these events were 
not associated with renal dysfunction and resolved with hydration and temporary interruption of 
therapy (e.g., 1–3 days).

Hyperbilirubinaemia 
Isolated asymptomatic hyperbilirubinaemia (total bilirubin  2.5 mg/dL, 43 mcmol/L) was reported 
predominantly as elevated indirect bilirubin and rarely associated with elevations in ALT, AST, or 
alkaline phosphatase, has occurred in approximately 14 % of patients treated with CRIXIVAN alone 
or in combination with other antiretroviral agents. Most patients continued treatment with CRIXIVAN
without dose reduction and bilirubin values gradually declined toward baseline. Hyperbilirubinaemia 
occurred more frequently at doses exceeding 2.4 g/day compared to doses less than 2.4 g/day. 

Paediatric population
In clinical trials in paediatric patients (≥ 3 years), the adverse reaction profile was similar to that for 
adult patients except for a higher frequency of nephrolithiasis of 29 % (20/70) in paediatric patients 
treated with CRIXIVAN. Asymptomatic pyuria of unknown etiology was noted in 10.9 % (6/55) of 
paediatric patients who received CRIXIVAN. Some of these events were associated with mild 
elevation of serum creatinine.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

 



45

professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

There have been reports of human overdose with CRIXIVAN. The most commonly reported 
symptoms were gastro-intestinal (e.g., nausea, vomiting, diarrhoea) and renal (e.g., nephrolithiasis, 
flank pain, haematuria).

It is not known whether indinavir is dialyzable by peritoneal or haemodialysis. 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitor, ATC code JO5AE02

Mechanism of action
Indinavir inhibits recombinant HIV–1 and HIV–2 protease with an approximate tenfold selectivity for 
HIV–1 over HIV–2 proteinase. Indinavir binds reversibly to the protease active site and inhibits 
competitively the enzyme, thereby preventing cleavage of the viral precursor polyproteins that occurs 
during maturation of the newly formed viral particle. The resulting immature particles are non–
infectious and are incapable of establishing new cycles of infection. Indinavir did not significantly 
inhibit the eukaryotic proteases human renin, human cathepsin D, human elastase, and human factor 
Xa.

Microbiology
Indinavir at concentrations of 50 to 100 nM mediated 95 % inhibition (IC95) of viral spread (relative 
to an untreated virus–infected control) in human T–lymphoid cell cultures and primary human 
monocytes/macrophages infected with HIV1 variants LAI, MN, RF, and a macrophage–tropic 
variant SF–162, respectively. Indinavir at concentrations of 25 to 100 nM mediated 95 % inhibition of 
viral spread in cultures of mitogen–activated human peripheral blood mononuclear cells infected with 
diverse, primary clinical isolates of HIV1, including isolates resistant to zidovudine and non–
nucleoside reverse transcriptase inhibitors (NNRTIs). Synergistic antiretroviral activity was observed 
when human T–lymphoid cells infected with the LAI variant of HIV–1 were incubated with indinavir 
and either zidovudine, didanosine, or NNRTIs.

Medicinal product resistance
Loss of suppression of viral RNA levels occurred in some patients; however, CD4 cell counts were 
often sustained above pre–treatment levels. When loss of viral RNA suppression occurred, it was 
typically associated with replacement of circulating susceptible virus with resistant viral variants. 
Resistance was correlated with the accumulation of mutations in the viral genome that resulted in the 
expression of amino acid substitutions in the viral protease.

At least eleven amino acid sites in the protease have been associated with indinavir resistance: L10, 
K20, L24, M46, I54, L63, I64, A71, V82, I84, and L90. The basis for their contributions to resistance, 
however, is complex. None of these substitutions was either necessary or sufficient for resistance. For 
example, no single substitution or pair of substitutions was capable of engendering measurable 
( four–fold) resistance to indinavir, and the level of resistance was dependent on the ways in which 
multiple substitutions were combined. In general, however, higher levels of resistance resulted from 
the co–expression of greater numbers of substitutions at the eleven identified positions. Among 
patients experiencing viral RNA rebound during indinavir monotherapy at 800 mg q8h, substitutions 
at only three of these sites were observed in the majority of patients: V82 (to A or F), M46 (to I or L), 
and L10 (to I or R). Other substitutions were observed less frequently. The observed amino acid 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


46

substitutions appeared to accumulate sequentially and in no consistent order, probably as a result of 
ongoing viral replication.

It should be noted that the decrease in suppression of viral RNA levels was seen more frequently 
when therapy with indinavir was initiated at doses lower than the recommended oral dose of 
2.4 g/day. Therefore, therapy with indinavir should be initiated at the recommended dose to 
increase suppression of viral replication and therefore inhibit the emergence of resistant virus.

The concomitant use of indinavir with nucleoside analogues (to which the patient is naive) may lessen 
the risk of the development of resistance to both indinavir and the nucleoside analogues. In one 
comparative trial, combination therapy with nucleoside analogues (triple therapy with zidovudine plus 
didanosine) conferred protection against the selection of virus expressing at least one resistance–
associated amino acid substitution to both indinavir (from 13/24 to 2/20 at therapy week 24) and to 
the nucleoside analogues (from 10/16 to 0/20 at therapy week 24).

Cross resistance
HIV1 patient isolates with reduced susceptibility to indinavir expressed varying patterns and degrees 
of cross–resistance to a series of diverse HIV PIs, including ritonavir and saquinavir. Complete 
crossresistance was noted between indinavir and ritonavir; however, crossresistance to saquinavir 
varied among isolates. Many of the protease amino acid substitutions reported to be associated with 
resistance to ritonavir and saquinavir were also associated with resistance to indinavir.

Pharmacodynamic effects 

Adults
Treatment with indinavir alone or in combination with other antiretroviral agents (i.e., nucleoside 
analogues) has so far been documented to reduce viral load and increase CD4 lymphocytes in patients 
with CD4 cell counts below 500 cells/mm3.

In one published study, 20 HIV-infected patients with undetectable plasma viral load 
(< 200 copies/mL) receiving indinavir 800 mg every 8 hours were switched in an open, cross-over 
design to indinavir/ritonavir 400/100 mg every 12 hours. Eighteen patients completed the study to 
week 48. Viral load remained < 200 copies/mL for 48 weeks in all patients. 

Another published study evaluated the efficacy and safety of indinavir/ritonavir 400/100 mg every 
12 hours in 40 antiretroviral-naïve patients. Thirty subjects completed 48 weeks of treatment. At 
week 4, the indinavir Cmin was 500 ng/mL with substantial trough variability (range 5 to 
8,100 ng/mL). By intent to treat analysis 65 % of patients had HIV RNA < 400 copies/mL and 50 % 
had viral load < 50 copies/mL; by on-treatment analysis 96 % of patients had HIV RNA 
< 400 copies/mL and 74 % had viral load < 50 copies/mL.

Eighty antiretroviral naïve patients were entered into a third published study. In this open label non-
randomized single arm study, patients were treated with stavudine and lamivudine plus 
indinavir/ritonavir 400/100 mg every 12 hours. Sixty-two patients completed the study to week 96. In 
the intent to treat and on treatment analyses the proportion of patients with HIV RNA of 
< 50 copies/mL was 68.8 % and 88.7 %, respectively, at week 96.

Indinavir alone or in combination with nucleoside analogues (zidovudine/stavudine and lamivudine) 
has been shown to delay clinical progression rate compared with nucleoside analogues and to provide 
a sustained effect on viral load and CD4 count.

In zidovudine experienced patients, indinavir, zidovudine and lamivudine in combination compared 
with lamivudine added to zidovudine reduced the probability of AIDS defining illness or death 
(ADID) at 48 weeks from 13 % to 7 %. Similarly, in antiretroviral naive patients, indinavir with and 
without zidovudine compared with zidovudine alone reduced the probability of ADID at 48 weeks 

 



47

from 15 % with zidovudine alone to approximately 6 % with indinavir alone or in combination with 
zidovudine.

Effects on viral load were consistently more pronounced in patients treated with indinavir in 
combination with nucleoside analogues, but the proportion of patients with serum viral RNA below 
the limit of quantification (500 copies/mL) varied between studies, at week 24 from 40 % to more 
than 80 %. This proportion tends to remain stable over prolonged periods of follow–up. Similarly, 
effects on CD4 cell count tend to be more pronounced in patients treated with indinavir in 
combination with nucleoside analogues compared with indinavir alone. Within studies, this effect is 
sustained also after prolonged periods of follow–up.

Paediatric population
Two clinical trials in 41 paediatric patients (4 to 15 years of age) were designed to characterise the 
safety, antiretroviral activity, and pharmacokinetics of indinavir in combination with stavudine and 
lamivudine. In one study, at week 24, the proportion of patients with plasma viral RNA below 
400 copies/mL was 60 %; the mean increase in CD4 cell counts was 242 cells/mm3; and the mean 
increase in percent CD4 cell counts was 4.2 %. At week 60, the proportion of patients with plasma 
viral RNA below 400 copies/mL was 59 %. In another study, at week 16, the proportion of patients
with plasma viral RNA below 400 copies/mL was 59 %; the mean increase in CD4 cell counts was 
73 cells/mm3; and the mean increase in percent CD4 cell counts was 1.2 %. At week 24, the 
proportion of patients with plasma viral RNA below 400 copies/mL was 60 %.

5.2 Pharmacokinetic properties

Absorption
Indinavir is rapidly absorbed in the fasted state with a time to peak plasma concentration of 0.8 hours 
± 0.3 hours (mean ± S.D.). A greater than dose–proportional increase in indinavir plasma 
concentrations was observed over the 200 – 800 mg dose range. Between 800–mg and 1,000–mg dose 
levels, the deviation from dose–proportionality is less pronounced. As a result of the short half–life, 
1.8 ± 0.4 hours, only a minimal increase in plasma concentrations occurred after multiple dosing. The 
bioavailability of a single 800–mg dose of indinavir was approximately 65 % (90 % CI, 58 – 72 %).

Data from a steady state study in healthy volunteers indicate that there is a diurnal variation in the 
pharmacokinetics of indinavir. Following a dose regimen of 800 mg every 8 hours, measured peak 
plasma concentrations (Cmax) after morning, afternoon and evening doses were 15,550 nM, 8,720 nM 
and 8,880 nM, respectively. Corresponding plasma concentrations at 8 hours post dose were 220 nM, 
210 nM and 370 nM, respectively. The relevance of these findings for ritonavir boosted indinavir is 
unknown. At steady state following a dose regimen of 800 mg every 8 hours, HIV–seropositive adult 
patients in one study achieved geometric means of: AUC0-8h of 27,813 nM*h (90 % confidence 
interval = 22,185, 34,869), peak plasma concentrations 11,144 nM (90 % confidence interval = 9,192, 
13,512) and plasma concentrations at 8 hours post dose 211 nM (90 % confidence interval = 
163,274).

Food effect
At steady state following a dose regimen of 800 mg/100 mg of indinavir/ritonavir every 12 hours with 
a low-fat meal, healthy volunteers in one study achieved geometric means: AUC0-12h 116,067 nM*h 
(90 % confidence interval = 101,680, 132,490), peak plasma concentrations 19,001 nM (90 % 
confidence interval = 17,538, 20,588), and plasma concentrations at 12 hours post dose 2,274 nM 
(90 % confidence interval = 1,701, 3,042). No significant difference in exposure was seen when the 
regimen was given with a high-fat meal.

Indinavir boosted regimen. Limited data are available on the pharmacokinetics of indinavir in 
association with low dose ritonavir. The pharmacokinetics of indinavir (400 mg) with ritonavir 
(100 mg) dosed twice daily was examined in two studies. Pharmacokinetic analysis in one study was 
performed on nineteen of the patients, with a median (range) indinavir AUC 0-12hr, Cmax, and Cmin 

 



48

of 25,421 nM*h (21,489 – 36,236 nM*h), 5,758 nM (5,056 – 6,742 nM) and 239 (169 – 421 nM), 
respectively. The pharmacokinetic parameters in the second study were comparable.

In HIVinfected paediatric patients, a dose regimen of indinavir hard capsules, 500 mg/m2 every 
8 hours, produced AUC0–8hr values of 27,412 nM*h, peak plasma concentrations of 12,182 nM, and 
plasma concentrations at 8 hours post dose of 122 nM. The AUC and peak plasma concentrations 
were generally similar to those previously observed in HIV–infected adults receiving the 
recommended dose of 800 mg every 8 hours; it should be observed that the plasma concentrations 
8 hours post dose were lower.

During pregnancy, it has been demonstrated that the systemic exposure of indinavir is relevantly 
decreased (PACTG 358. Crixivan, 800 mg every 8 hours + zidovudine 200 mg every 8 hours and 
lamivudine 150 mg twice a day). The mean indinavir plasma AUC0-8hr at week 30-32 of gestation 
(n = 11) was 9,231 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 section 4.6).

Administration of indinavir with a meal high in calories, fat, and protein resulted in a blunted and 
reduced absorption with an approximate 80 % reduction in AUC and an 86 % reduction in Cmax. 
Administration with light meals (e.g., dry toast with jam or fruit conserve, apple juice, and coffee with 
skimmed or fat–free milk and sugar or corn flakes, skimmed or fat–free milk and sugar) resulted in 
plasma concentrations comparable to the corresponding fasted values.

The pharmacokinetics of indinavir taken as indinavir sulphate salt (from opened hard capsules) mixed 
in apple sauce were generally comparable to the pharmacokinetics of indinavir taken as hard capsules, 
under fasting conditions. In HIV–infected paediatric patients, the pharmacokinetic parameters of 
indinavir in apple sauce were: AUC0–8hr of 26,980 nM*h; peak plasma concentration of 13,711 nM; 
and plasma concentration at 8 hours post dose of 146 nM.

Distribution
Indinavir was not highly bound to human plasma proteins (39 % unbound). 

There are no data concerning the penetration of indinavir into the central nervous system in humans.

Biotransformation
Seven major metabolites were identified and the metabolic pathways were identified as 
glucuronidation at the pyridine nitrogen, pyridine–N–oxidation with and without 3’–hydroxylation on 
the indane ring, 3’–hydroxylation of indane, p–hydroxylation of phenylmethyl moiety, and 
N-depyridomethylation with and without the 3’–hydroxylation. In vitro studies with human liver 
microsomes indicated that CYP3A4 is the only P450 isozyme that plays a major role in the oxidative 
metabolism of indinavir. Analysis of plasma and urine samples from subjects who received indinavir 
indicated that indinavir metabolites had little proteinase inhibitory activity.

Elimination
Over the 200–1,000–mg dose range administered in both volunteers and HIV infected patients, there 
was a slightly greater than dose–proportional increase in urinary recovery of indinavir. Renal 
clearance (116 mL/min) of indinavir is concentration–independent over the clinical dose range. Less 
than 20 % of indinavir is excreted renally. Mean urinary excretion of unchanged medicinal product 
following single dose administration in the fasted state was 10.4 % following a 700–mg dose, and 
12.0 % following a 1,000–mg dose. Indinavir was rapidly eliminated with a half–life of 1.8 hours.

Characteristics in patients
Pharmacokinetics of indinavir do not appear to be affected by race.

 



49

There are no clinically significant differences in the pharmacokinetics of indinavir in HIV 
seropositive women compared to HIV seropositive men. 

Patients with mild–to–moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence 
of decreased metabolism of indinavir resulting in approximately 60 % higher mean AUC following a 
400–mg dose. The mean half–life of indinavir increased to approximately 2.8 hours.

5.3 Preclinical safety data

Crystals have been seen in the urine of rats, one monkey, and one dog. The crystals have not been 
associated with medicinal product –induced renal injury. An increase in thyroidal weight and 
thyroidal follicular cell hyperplasia, due to an increase in thyroxine clearance, was seen in rats treated 
with indinavir at doses  160 mg/kg/day. An increase in hepatic weight occurred in rats treated with 
indinavir at doses  40 mg/kg/day and was accompanied by hepatocellular hypertrophy at doses 
 320 mg/kg/day. 

The maximum non–lethal oral dose of indinavir was at least 5,000 mg/kg in rats and mice, the highest 
dose tested in acute toxicity studies.

Studies in rats indicated that uptake into brain tissue was limited, distribution into and out of the 
lymphatic system was rapid, and excretion into the milk of lactating rats was extensive. Distribution 
of indinavir across the placental barrier was significant in rats, but limited in rabbits.

Mutagenicity
Indinavir did not have any mutagenic or genotoxic activity in studies with or without metabolic 
activation.

Carcinogenicity
No carcinogenicity was noted in mice at the maximum tolerated dose, which corresponded to a 
systemic exposure approximately 2 to 3 times higher than the clinical exposure. In rats, at similar 
exposure levels, an increased incidence of thyroid adenomas was seen, probably related to an increase 
in release of thyroid stimulating hormone secondary to an increase in thyroxine clearance. The 
relevance of the findings to humans is likely limited.

Developmental Toxicity
Developmental toxicity studies were performed in rats, rabbits and dogs (at doses which produced 
systemic exposures comparable to or slightly greater than human exposure) and revealed no evidence 
of teratogenicity. No external or visceral changes were observed in rats, however, increases in the 
incidence of supernumerary ribs and of cervical ribs were seen. No external, visceral, or skeletal 
changes were observed in rabbits or dogs. In rats and rabbits, no effects on embryonic/foetal survival 
or foetal weights were observed. In dogs, a slight increase in resorptions was seen; however, all 
foetuses in medication-treated animals were viable, and the incidence of live foetuses in 
medication-treated animals was comparable to that in controls.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
anhydrous lactose 
magnesium stearate

Capsule shell:
gelatin
titanium dioxide (E 171)

 



50

printing ink: titanium dioxide (E 171), indigo carmine (E 132) and iron oxide (E 172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years for HDPE bottles containing 90 and 180 hard capsules.

6.4 Special precautions for storage

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. 

6.5 Nature and contents of container

HDPE bottles with a polypropylene cap and a foil induction cap containing 90 or 180 capsules.

Not all pack sizes may be marketed. 

6.6 Special precautions for disposal and other handling

The bottles contain desiccant canisters that should remain in the container. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/96/024/004
EU/1/96/024/005

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 04 October 1996
Date of latest renewal: 18 July 2011

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 



51

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT

 



52

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Merck Sharp & Dohme B.V., Waarderweg 39, P.O. Box 581, 2003 PC Haarlem, The Netherlands

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

Not applicable.

 



53

ANNEX III

LABELLING AND PACKAGE LEAFLET

 



54

A. LABELLING

 



55

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CRIXIVAN 200 mg – packs of 180, 270 and 360 capsules – Outer carton 

1. NAME OF THE MEDICINAL PRODUCT

CRIXIVAN 200 mg hard capsules
Indinavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Anhydrous lactose. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

180 hard capsules
270 hard capsules
360 hard capsules

5. METHOD AND ROUTES OF ADMINISTRATION

Read the package leaflet before use.
Oral use.
Hard capsules should be swallowed whole.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Desiccant should not be removed from the container.
Desiccant should not be swallowed.

8. EXPIRY DATE

EXP

 



56

9. SPECIAL STORAGE CONDITIONS:

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/96/024/001 180 hard capsules
EU/1/96/024/002 270 hard capsules
EU/1/96/024/003 360 hard capsules

13. BATCH NUMBER

Batch 

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

CRIXIVAN 200 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN: 
NN:

 



57

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

CRIXIVAN 200 mg – packs of 180, 270 and 360 capsules – Bottle label

1. NAME OF THE MEDICINAL PRODUCT

CRIXIVAN 200 mg hard capsules
Indinavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Anhydrous lactose. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

180 hard capsules
270 hard capsules
360 hard capsules

5. METHOD AND ROUTES OF ADMINISTRATION

Read the package leaflet before use.
Oral use.
Hard capsules should be swallowed whole.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Desiccant should not be removed from the container.
Desiccant should not be swallowed.

8. EXPIRY DATE

EXP

 



58

9. SPECIAL STORAGE CONDITIONS:

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/96/024/001 180 hard capsules
EU/1/96/024/002 270 hard capsules
EU/1/96/024/003 360 hard capsules

13. BATCH NUMBER

Batch 

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

 



59

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CRIXIVAN 400 mg – packs of 90 and 180 capsules – Outer carton 

1. NAME OF THE MEDICINAL PRODUCT

CRIXIVAN 400 mg hard capsules
Indinavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Anhydrous lactose. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

90 hard capsules
180 hard capsules

5. METHOD AND ROUTES OF ADMINISTRATION

Read the package leaflet before use.
Oral use. 
Hard capsules should be swallowed whole.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Desiccant should not be removed from the container.
Desiccant should not be swallowed.

8. EXPIRY DATE

EXP

 



60

9. SPECIAL STORAGE CONDITIONS:

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/96/024/004 90 hard capsules
EU/1/96/024/005 180 hard capsules

13. BATCH NUMBER

Batch 

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

CRIXIVAN 400 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN: 
NN:

 



61

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

CRIXIVAN 400 mg – packs of 90 and 180 capsules – Bottle label

1. NAME OF THE MEDICINAL PRODUCT

CRIXIVAN 400 mg hard capsules
Indinavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

3. LIST OF EXCIPIENTS

Anhydrous lactose. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

90 hard capsules
180 hard capsules

5. METHOD AND ROUTES OF ADMINISTRATION

Read the package leaflet before use.
Oral use. 
Hard capsules should be swallowed whole.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Desiccant should not be removed from the container.
Desiccant should not be swallowed.

8. EXPIRY DATE

EXP

 



62

9. SPECIAL STORAGE CONDITIONS:

Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/96/024/004 90 hard capsules
EU/1/96/024/005 180 hard capsules

13. BATCH NUMBER

Batch 

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

 



63

B. PACKAGE LEAFLET

 



64

Package leaflet: Information for the user

CRIXIVAN 200 mg hard capsules
indinavir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, ask your doctor, pharmacist or nurse.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What CRIXIVAN is and what it is used for
2. What you need to know before you take CRIXIVAN
3. How to take CRIXIVAN
4. Possible side effects
5. How to store CRIXIVAN
6. Contents of the pack and other information

1. What CRIXIVAN is and what it is used for

What CRIXIVAN is
CRIXIVAN contains a substance called indinavir. It belongs to a group of medicines called ‘protease 
inhibitors’. 

What CRIXIVAN is used for
CRIXIVAN is used to treat Human Immunodeficiency Virus (HIV) in adults. CRIXIVAN is used at 
the same time as other HIV treatments (antiretroviral medicines). This is called combination 
antiretroviral therapy. 

 An example of another medicine that might be given to you, at the same time as CRIXIVAN, 
is ritonavir. 

How CRIXIVAN works
CRIXIVAN treats HIV and helps to lower the number of HIV particles in your blood.

CRIXIVAN helps to:
 lower the risk that you get illnesses related to HIV 
 lower the amount of HIV in your body (your ‘viral load’)
 raise your CD4 (T) cell count. CD4 cells are an important part of your immune system. The 

main role of the immune system is to protect you from infections. 
CRIXIVAN may not do these things in all patients. Your doctor will monitor how this medicine 
works for you.

2. What you need to know before you take CRIXIVAN

Do not take CRIXIVAN:
 if you are allergic to indinavir or any of the other ingredients of this medicine (listed in 

Section 6). 
 if you are taking any of the following medicines:

 



65

- rifampicin - an antibiotic used to treat infections
- cisapride - used for gut problems
- amiodarone - used for heart rhythm problems
- pimozide - used for some mental health problems
- lovastatin or simvastatin - used to lower cholesterol
- St. John's wort (Hypericum perforatum) - a herbal medicine used for depression
- ergot tartramine (with or without caffeine) - used for migraines
- astemizole or terfenadine - antihistamines used for hay fever and other allergies
- quetiapine – used for some mental illnesses such as schizophrenia, bipolar 

disorder and major depressive disorder
- alprazolam, triazolam and midazolam (by mouth) - used to make you calmer or 

help you sleep.

Do not take CRIXIVAN if any of the above applies to you. If you are not sure, talk to your doctor, 
pharmacist or nurse before taking CRIXIVAN.

In addition, when CRIXIVAN is given at the same time as the medicine ritonavir:
Do not take either CRIXIVAN or ritonavir:

 if you have liver problems 
 if you are taking any of the following medicines:

- fusidic acid - an antibiotic used to treat infections
- piroxicam - used for arthritis
- alfuzosin - used for prostate problems
- bepridil - used for chest pain (angina)
- clozapine - used for some mental health problems 
- pethidine or propoxyphene - used for pain
- estazolam or flurazepam - used to help you sleep
- clorazepate or diazepam - used to make you calmer
- encainide, flecanide, propafenone, or quinidine - used for uneven heartbeat 

problems.

Do not take either CRIXIVAN or ritonavir if any of the above applies to you. If you are not sure, talk 
to your doctor, pharmacist or nurse before taking CRIXIVAN.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking CRIXIVAN if you have had or develop any of 
the following:

 allergies

 kidney problems (including inflammation of the kidneys, kidney stones, or back pain with or 
without blood in your urine)

 ‘haemophilia’ – CRIXIVAN may make you more likely to bleed. If you notice bleeding or if you 
feel weak, talk to your doctor straight away.

 liver problems – people with ‘chronic hepatitis B or C’ or ‘cirrhosis’ who are treated with 
‘antiretroviral’ medicines are more likely to have serious and potentially fatal liver side effects 
with this medicine. You may need to have blood tests to check how your liver is working.

 severe pain, tenderness or weakness in your muscles – this is more likely to happen if you are 
taking cholesterol-lowering medicines called ‘statins’ (such as simvastatin). On rare occasions the 
muscle problems can be serious (rhabdomyolysis). Inform your doctor as soon as possible if you 
develop severe muscle pain or weakness.

 



66

 signs of infection – this may be a previous infection which comes back soon after anti-HIV 
treatment is started. This may be because the body is able to start fighting infections again. This 
happens in some people with advanced HIV infection (AIDS) and who have had HIV related 
infections before. If you notice any symptoms of infection, please inform your doctor 
immediately.

 autoimmune disorders (a condition that occurs when the immune system attacks healthy body 
tissue) may also occur after you start taking medicines for the treatment of your HIV infection. 
Autoimmune disorders may occur many months after the start of treatment. If you notice any 
symptoms of infection or other symptoms such as muscle weakness, weakness beginning in the 
hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, 
please inform your doctor immediately to seek necessary treatment.

 bone problems – signs include stiff joints, aches and pains, especially the hip and difficulty 
moving. If you notice any of these signs, talk to your doctor. Such problems might be due to a 
bone disease called ‘osteonecrosis’ (loss of blood supply to the bone causing bone death), which 
can occur months to years after starting HIV therapy. The risk of you having bone problems is 
higher if you:
- drink alcohol
- have a high body mass index
- have an immune system that is very weak
- have been taking corticosteroids at the same time as CRIXIVAN
- take combination antiretroviral therapy for a long time.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking CRIXIVAN.

Children and adolescents
CRIXIVAN is not recommended in children under the age of 18 years.

Other medicines and CRIXIVAN
Tell your doctor, pharmacist or nurse if you are taking, have recently taken, or might take any other 
medicines. This includes medicines obtained without a prescription, including herbal medicines.

CRIXIVAN can affect the way some other medicines work. Also some other medicines can affect the 
way CRIXIVAN works.

Ritonavir
Ritonavir is used for increasing the blood levels of CRIXIVAN or, less frequently and then at higher 
doses, for HIV treatment. Talk to your doctor if you are going to take both CRIXIVAN and ritonavir. 
Also look at the Package Leaflet for ritonavir.

Please see ‘Do not take CRIXIVAN’ and ‘Do not take either CRIXIVAN or ritonavir’ above 
under Section 2 for an important list of medicines that you must not combine with CRIXIVAN. Do 
not take CRIXIVAN if you are taking or have recently taken any of these medicines. If you are not 
sure, talk to your doctor, pharmacist or nurse before taking CRIXIVAN.

In addition, talk to your doctor, pharmacist or nurse before taking CRIXIVAN if you are 
taking any of the following medicines since your doctor may want to adjust the dose of your 
medicines:

 theophylline - used for asthma
 warfarin - used to thin the blood
 morphine, fentanyl - used for pain
 buspirone - used to make you calmer
 fluconazole - used for fungal infections

 



67

 venlafaxine, trazodone - used for depression
 tacrolimus, ciclosporin - used mainly after organ transplantation
 delavirdine, efavirenz, nevirapine - used for HIV
 amprenavir, saquinavir, atazanavir - used for HIV
 sildenafil, vardenafil, tadalafil - used for impotence
 dexamethasone - used to stop swelling (inflammation)
 itraconazole, ketoconazole - used to treat fungal infections
 atorvastatin, rosuvastatin, pravastatin, fluvastatin - used to lower cholesterol
 fexofenadine, loratidine - antihistamines used for hay fever and other allergic conditions
 oral contraceptive medicines (‘The Pill’) containing norethindrone or ethinyl estradiol
 phenobarbital, phenytoin, carbamazepine, divalproex, lamotrigine - medicines used to treat 

fits (epilepsy)
 midazolam (by injection) - used for acute fits (seizures) and to send patients to sleep before 

some medical procedures
 amlodipine, felodipine, nifedipine, nicardipine, digoxin, diltiazem - used for high blood 

pressure and some heart problems.
 quetiapine – used for some mental illnesses such as schizophrenia, bipolar disorder and major 

depressive disorder

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking CRIXIVAN.

CRIXIVAN with food and drink
See Section 3 below for information on how to take CRIXIVAN. It is however especially important 
that you:

 do not take CRIXIVAN with food that is high in calories, fat and protein. This is because these 
foods stop your body being able to take in as much CRIXIVAN and it will not work as well.

Pregnancy and breast-feeding
 If you are pregnant, think you may be pregnant or are planning to have a baby, only take 

CRIXIVAN if your doctor decides it is clearly necessary. It is not known whether CRIXIVAN 
is harmful to an unborn baby when taken by a pregnant woman.

 It is recommended that women with HIV do not breast-feed. This is to stop HIV being passed 
on to their baby.

Driving and using machines
Dizziness and blurred vision have been reported during treatment with CRIXIVAN. If this happens, 
do not drive or operate machines.

Other things you should know
CRIXIVAN is not a cure for HIV. You may still get infections or other illnesses related to HIV. So 
you still need to keep seeing your doctor while you are taking CRIXIVAN.

HIV is spread by blood or sexual contact with a person with HIV. You can still pass on HIV when 
taking this medicine, although the risk is lowered by effective antiretroviral therapy. Discuss with 
your physician the precautions needed to avoid infecting other people.

CRIXIVAN contains lactose
This medicine contains lactose (type of sugar). If you have been told by your doctor that you cannot 
tolerate or digest some sugars, talk to your doctor before taking this medicine.

 



68

3. How to take CRIXIVAN

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your 
doctor, pharmacist or nurse if you are not sure.

How much to take

The recommended dose of CRIXIVAN is:
 Four 200 mg capsules (800 mg) - taken three times a day (every 8 hours).

This means you will take a total of twelve 200 mg capsules (2400 mg) each day.

You usually take less CRIXIVAN if you are also taking ritonavir. The recommended doses are:
 CRIXIVAN - two 200 mg capsules (400 mg) - taken twice a day.

This means you will take a total of four 200 mg capsules (800 mg) each day.
 ritonavir - 100 mg - taken twice a day.

Taking this medicine
 Take this medicine by mouth.
 Swallow the capsules whole with a drink of water, skimmed or low fat milk, juice, tea or 

coffee.
 Do not crush or chew the capsules.
 It is important for adults to drink at least 1.5 litres of liquid each day while taking CRIXIVAN.

This will help lower the risk of you getting kidney stones.
 Do not take CRIXIVAN with food that is high in calories, fat and protein. This is because these 

stop your body being able to take in as much CRIXIVAN and it will not work as well.

When to take
 Take 1 hour before or 2 hours after a meal.
 If you cannot take it without food then take CRIXIVAN with a low-fat light meal. This could 

be dry toast with jam or cornflakes with skimmed or low-fat milk and sugar.
 If you are also taking ritonavir, then you can take CRIXIVAN at any time of the day with or 

without food.

If you take more CRIXIVAN than you should
If you take more CRIXIVAN than you should, talk to your doctor as soon as possible. The following 
effects may happen:
 nausea
 vomiting
 diarrhoea
 back pain
 blood in your urine.

If you forget to take CRIXIVAN
Do not take a double dose to make up for a forgotten dose. If you have missed a dose, do not take it 
later in the day. Simply continue to follow your usual schedule. 

If you stop taking CRIXIVAN
It is important that you take CRIXIVAN exactly as your doctor tells you to - he or she will tell you 
how long you should take your medicine. 
 Do not stop taking CRIXIVAN without talking to your doctor.
 This is because reducing or missing doses will make it more likely that HIV will become

resistant to CRIXIVAN.
 If this happens, your treatment will stop working.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

 



69

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effects have been reported by patients taking CRIXIVAN:

See your doctor straight away if you notice any of the following serious side effects - you may 
need urgent medical treatment:
 allergic reactions - signs include itchy skin, redness of the skin, ‘wheals’ or ‘hives’, swelling of 

the face, lips, tongue or throat and difficulty breathing. It is not known how often this may 
happen (cannot be estimated from the available data), but the reaction can sometimes be severe 
and include shock

There are also other side effects that you may get while taking this medicine such as increased 
bleeding in haemophiliacs, muscle problems, signs of infection, and bone problems. Please see 
‘Warnings and precautions’ in Section 2 above.

Additional side effects include:

Very common (affects more than 1 in 10 people): 
 headache
 rash or dry skin
 nausea
 vomiting
 altered taste sensations
 indigestion or diarrhoea
 stomach pain or swelling
 feeling dizzy, weak or tired.

Common (affects less than 1 in 10 people):
 passing gas
 itching
 dry mouth
 acid reflux
 muscle pain
 pain on urination
 difficulty getting to sleep
 feeling numb or unusual feeling of the skin.

The following side effects have also been reported since the medicine has been used. How 
often they happen is not known:
 hair loss
 inflamed pancreas
 severe skin reactions
 darkening skin colour
 having a numb mouth
 low red blood cell count
 ingrown toenails with or without infection

 



70

 liver problems such as inflammation or liver failure
 kidney problems such as kidney infection, worsening or loss of kidney function
 pain and difficulty moving shoulder.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store CRIXIVAN

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle or carton after ‘EXP’. The 
expiry date refers to the last day of that month.

Store CRIXIVAN in the original bottle and keep the bottle tightly closed to protect it from moisture. 
The bottle contains desiccant canisters that should remain in the bottle.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What CRIXIVAN contains

 The active substance is indinavir. Each hard capsule contains indinavir sulphate corresponding 
to 200 mg of indinavir.

 The other ingredients are anhydrous lactose, magnesium stearate, gelatin and titanium dioxide 
(E 171). 

 The capsules are printed with printing ink containing indigo carmine (E 132).

What CRIXIVAN looks like and contents of the pack

CRIXIVAN 200 mg hard capsules are supplied in HDPE bottles with a polypropylene cap and a foil 
seal containing 180, 270 or 360 capsules. Not all pack sizes may be marketed.

The capsules are semi-translucent white and coded ‘CRIXIVAN 200 mg’ on them in blue.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem,
The Netherlands

Manufacturer: Merck Sharp & Dohme B.V., Waarderweg 39, Postbus 581, 2003 PC Haarlem
The Netherlands

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


71

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България 
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland 
Merck Sharp & Dohme BV
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@ msd.no

Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
clic@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 29 00
msdromania@merck.com

 



72

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o.
Tel: + 386 1 5204 201
msd_slovenia@merck.com

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 800 00 673 (+357 22866700)
cyprus_info@merck.com 

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364224
msd_lv@merck.com.

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in 

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.

 



73

Package leaflet: Information for the user

CRIXIVAN 400 mg hard capsules
indinavir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, ask your doctor, pharmacist or nurse.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What CRIXIVAN is and what it is used for
2. What you need to know before you take CRIXIVAN
3. How to take CRIXIVAN
4. Possible side effects
5. How to store CRIXIVAN
6. Contents of the pack and other information

1. What CRIXIVAN is and what it is used for

What CRIXIVAN is
CRIXIVAN contains a substance called indinavir. It belongs to a group of medicines called ‘protease 
inhibitors’. 

What CRIXIVAN is used for
CRIXIVAN is used to treat Human Immunodeficiency Virus (HIV) in adults. CRIXIVAN is used at 
the same time as other HIV treatments (antiretroviral medicines). This is called combination
antiretroviral therapy. 

 An example of another medicine that might be given to you, at the same time as CRIXIVAN, 
is ritonavir. 

How CRIXIVAN works
CRIXIVAN treats HIV and helps to lower the number of HIV particles in your blood.

CRIXIVAN helps to:
 lower the risk that you get illnesses related to HIV 
 lower the amount of HIV in your body (your ‘viral load’)
 raise your CD4 (T) cell count. CD4 cells are an important part of your immune system. The 

main role of the immune system is to protect you from infections. 
CRIXIVAN may not do these things in all patients. Your doctor will monitor how this medicine 
works for you.

2. What you need to know before you take CRIXIVAN

Do not take CRIXIVAN:
 if you are allergic to indinavir or any of the other ingredients of this medicine (listed in 

Section 6). 
 if you are taking any of the following medicines:

 



74

- rifampicin - an antibiotic used to treat infections
- cisapride - used for gut problems
- amiodarone - used for heart rhythm problems
- pimozide - used for some mental health problems
- lovastatin or simvastatin - used to lower cholesterol
- St. John's wort (Hypericum perforatum) - a herbal medicine used for depression
- ergot tartramine (with or without caffeine) - used for migraines
- astemizole or terfenadine - antihistamines used for hay fever and other allergies
- quetiapine – used for some mental illnesses such as schizophrenia, bipolar 

disorder and major depressive disorder
- alprazolam, triazolam and midazolam (by mouth) - used to make you calmer or 

help you sleep.

Do not take CRIXIVAN if any of the above applies to you. If you are not sure, talk to your doctor, 
pharmacist or nurse before taking CRIXIVAN.

In addition, when CRIXIVAN is given at the same time as the medicine ritonavir:
Do not take either CRIXIVAN or ritonavir:

 if you have liver problems 
 if you are taking any of the following medicines:

- fusidic acid - an antibiotic used to treat infections
- piroxicam - used for arthritis
- alfuzosin - used for prostate problems
- bepridil - used for chest pain (angina)
- clozapine - used for some mental health problems 
- pethidine or propoxyphene - used for pain
- estazolam or flurazepam - used to help you sleep
- clorazepate or diazepam - used to make you calmer
- encainide, flecanide, propafenone, or quinidine - used for uneven heartbeat 

problems.

Do not take either CRIXIVAN or ritonavir if any of the above applies to you. If you are not sure, talk 
to your doctor, pharmacist or nurse before taking CRIXIVAN.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking CRIXIVAN if you have had or develop any of 
the following:

 allergies

 kidney problems (including inflammation of the kidneys, kidney stones, or back pain with or 
without blood in your urine)

 ‘haemophilia’ – CRIXIVAN may make you more likely to bleed. If you notice bleeding or if you 
feel weak, talk to your doctor straight away.

 liver problems – people with ‘chronic hepatitis B or C’ or ‘cirrhosis’ who are treated with 
‘antiretroviral’ medicines are more likely to have serious and potentially fatal liver side effects 
with this medicine. You may need to have blood tests to check how your liver is working.

 severe pain, tenderness or weakness in your muscles – this is more likely to happen if you are 
taking cholesterol-lowering medicines called ‘statins’ (such as simvastatin). On rare occasions the 
muscle problems can be serious (rhabdomyolysis). Inform your doctor as soon as possible if you 
develop severe muscle pain or weakness.

 



75

 signs of infection – this may be a previous infection which comes back soon after anti-HIV 
treatment is started. This may be because the body is able to start fighting infections again. This 
happens in some people with advanced HIV infection (AIDS) and who have had HIV related 
infections before. If you notice any symptoms of infection, please inform your doctor 
immediately.

 autoimmune disorders (a condition that occurs when the immune system attacks healthy body 
tissue) may also occur after you start taking medicines for the treatment of your HIV infection. 
Autoimmune disorders may occur many months after the start of treatment. If you notice any 
symptoms of infection or other symptoms such as muscle weakness, weakness beginning in the 
hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, 
please inform your doctor immediately to seek necessary treatment.

 bone problems – signs include stiff joints, aches and pains, especially of the hip and difficulty 
moving. If you notice any of these signs, talk to your doctor. Such problems might be due to a 
bone disease called ‘osteonecrosis’ (loss of blood supply to the bone causing bone death), which 
can occur months to years after starting HIV therapy. The risk of you having bone problems is 
higher if you:
- drink alcohol
- have a high body mass index
- have an immune system that is very weak
- have been taking corticosteroids at the same time as CRIXIVAN
- take combination antiretroviral therapy for a long time.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking CRIXIVAN.

Children and adolescents
CRIXIVAN is not recommended in children under the age of 18 years.

Other medicines and CRIXIVAN
Tell your doctor, pharmacist or nurse if you are taking, have recently taken, or might take any other 
medicines. This includes medicines obtained without a prescription, including herbal medicines.

CRIXIVAN can affect the way some other medicines work. Also some other medicines can affect the 
way CRIXIVAN works.

Ritonavir
Ritonavir is used for increasing the blood levels of CRIXIVAN or, less frequently and then at higher 
doses, for HIV treatment. Talk to your doctor if you are going to take both CRIXIVAN and ritonavir. 
Also look at the Package Leaflet for ritonavir.

Please see ‘Do not take CRIXIVAN’ and ‘Do not take either CRIXIVAN or ritonavir’ above 
under Section 2 for an important list of medicines that you must not combine with CRIXIVAN. Do 
not take CRIXIVAN if you are taking or have recently taken any of these medicines. If you are not 
sure, talk to your doctor, pharmacist or nurse before taking CRIXIVAN.

In addition, talk to your doctor, pharmacist or nurse before taking CRIXIVAN if you are 
taking any of the following medicines since your doctor may want to adjust the dose of your 
medicines:

 theophylline - used for asthma
 warfarin - used to thin the blood
 morphine, fentanyl - used for pain
 buspirone - used to make you calmer
 fluconazole - used for fungal infections

 



76

 venlafaxine, trazodone - used for depression
 tacrolimus, ciclosporin - used mainly after organ transplantation
 delavirdine, efavirenz, nevirapine - used for HIV
 amprenavir, saquinavir, atazanavir - used for HIV
 sildenafil, vardenafil, tadalafil - used for impotence
 dexamethasone - used to stop swelling (inflammation)
 itraconazole, ketoconazole - used to treat fungal infections
 atorvastatin, rosuvastatin, pravastatin, fluvastatin - used to lower cholesterol
 fexofenadine, loratidine - antihistamines used for hay fever and other allergic conditions
 oral contraceptive medicines (‘The Pill’) containing norethindrone or ethinyl estradiol
 phenobarbital, phenytoin, carbamazepine, divalproex, lamotrigine - medicines used to treat 

fits (epilepsy)
 midazolam (by injection) - used for acute fits (seizures) and to send patients to sleep before 

some medical procedures
 amlodipine, felodipine, nifedipine, nicardipine, digoxin, diltiazem - used for high blood 

pressure and some heart problems.
 quetiapine – used for some mental illnesses such as schizophrenia, bipolar disorder and major 

depressive disorder

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking CRIXIVAN.

CRIXIVAN with food and drink
See Section 3 below for information on how to take CRIXIVAN. It is however especially important 
that you:

 do not take CRIXIVAN with food that is high in calories, fat and protein. This is because these 
foods stop your body being able to take in as much CRIXIVAN and it will not work as well.

Pregnancy and breast-feeding
 If you are pregnant, think you may be pregnant or are planning to have a baby, only take 

CRIXIVAN if your doctor decides it is clearly necessary. It is not known whether CRIXIVAN 
is harmful to an unborn baby when taken by a pregnant woman.

 It is recommended that women with HIV do not breast-feed. This is to stop HIV being passed 
on to their baby.

Driving and using machines
Dizziness and blurred vision have been reported during treatment with CRIXIVAN. If this happens, 
do not drive or operate machines.

Other things you should know
CRIXIVAN is not a cure for HIV. You may still get infections or other illnesses related to HIV. So 
you still need to keep seeing your doctor while you are taking CRIXIVAN.

HIV is spread by blood or sexual contact with a person with HIV. You can still pass on HIV when 
taking this medicine, although the risk is lowered by effective antiretroviral therapy. Discuss with 
your physician the precautions needed to avoid infecting other people.

CRIXIVAN contains lactose
This medicine contains lactose (type of sugar). If you have been told by your doctor that you cannot 
tolerate or digest some sugars, talk to your doctor before taking this medicine.

 



77

3. How to take CRIXIVAN

Always take this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your 
doctor, pharmacist or nurse if you are not sure.

How much to take

The recommended dose of CRIXIVAN is:
 Two 400 mg capsules (800 mg) - taken three times a day (every 8 hours).

This means you will take a total of six 400 mg capsules (2400 mg) each day.

You usually take less CRIXIVAN if you are also taking ritonavir. The recommended doses are:
 CRIXIVAN – one 400 mg capsules (400 mg) - taken twice a day.

This means you will take a total of two 400 mg capsules (800 mg) each day.
 ritonavir - 100 mg - taken twice a day.

Taking this medicine
 Take this medicine by mouth.
 Swallow the capsules whole with a drink of water, skimmed or low fat milk, juice, tea or 

coffee.
 Do not crush or chew the capsules.
 It is important for adults to drink at least 1.5 litres of liquid each day while taking CRIXIVAN. 

This will help lower the risk of you getting kidney stones.
 Do not take CRIXIVAN with food that is high in calories, fat and protein. This is because these 

stop your body being able to take in as much CRIXIVAN and it will not work as well.

When to take
 Take 1 hour before or 2 hours after a meal.
 If you cannot take it without food then take CRIXIVAN with a low-fat light meal. This could 

be dry toast with jam or cornflakes with skimmed or low-fat milk and sugar.
 If you are also taking ritonavir, then you can take CRIXIVAN at any time of the day with or 

without food.

If you take more CRIXIVAN than you should
If you take more CRIXIVAN than you should, talk to your doctor as soon as possible. The following 
effects may happen:
 nausea
 vomiting
 diarrhoea
 back pain
 blood in your urine.

If you forget to take CRIXIVAN
Do not take a double dose to make up for a forgotten dose. If you have missed a dose, do not take it 
later in the day. Simply continue to follow your usual schedule. 

If you stop taking CRIXIVAN
It is important that you take CRIXIVAN exactly as your doctor tells you to - he or she will tell you 
how long you should take your medicine. 
 Do not stop taking CRIXIVAN without talking to your doctor. 
 This is because reducing or missing doses will make it more likely that HIV will become 

resistant to CRIXIVAN. 
 If this happens, your treatment will stop working.

If you have any further questions on the use of thismedicine, ask your doctor, pharmacist, or nurse.

 



78

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effects have been reported by patients taking CRIXIVAN:

See your doctor straight away if you notice any of the following serious side effects - you may 
need urgent medical treatment:
 allergic reactions - signs include itchy skin, redness of the skin, ‘wheals’ or ‘hives’, swelling of 

the face, lips, tongue or throat and difficulty breathing. It is not known how often this may 
happen (cannot be estimated from the available data), but the reaction can sometimes be severe 
and include shock

There are also other side effects that you may get while taking this medicine such as increased 
bleeding in haemophiliacs, muscle problems, signs of infection, and bone problems. Please see 
‘Warnings and precautions’ in Section 2 above.

Additional side effects include:

Very common (affects more than 1 in 10 people): 
 headache
 rash or dry skin 
 nausea
 vomiting
 altered taste sensations
 indigestion or diarrhoea
 stomach pain or swelling
 feeling dizzy, weak or tired.

Common (affects less than 1 in 10 people):
 passing gas
 itching
 dry mouth
 acid reflux
 muscle pain
 pain on urination
 difficulty getting to sleep
 feeling numb or unusual feeling of the skin.

The following side effects have also been reported since the medicine has been used. How 
often they happen is not known:
 hair loss
 inflamed pancreas
 severe skin reactions
 darkening skin colour
 having a numb mouth
 low red blood cell count
 ingrown toenails with or without infection

 



79

 liver problems such as inflammation or liver failure
 kidney problems such as kidney infection, worsening or loss of kidney function
 pain and difficulty moving shoulder.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store CRIXIVAN

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle or carton after ‘EXP’. The 
expiry date refers to the last day of that month.

Store CRIXIVAN in the original bottle and keep the bottle tightly closed to protect it from moisture. 
The bottle contains desiccant canisters that should remain in the bottle.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What CRIXIVAN contains

 The active substance is indinavir. Each hard capsule contains indinavir sulphate corresponding 
to 400 mg of indinavir.

 The other ingredients are anhydrous lactose, magnesium stearate, gelatin and titanium dioxide 
(E 171).

 The capsules are printed with printing ink containing titanium dioxide (E 171), indigo carmine 
(E 132) and iron oxide (E 172).

What CRIXIVAN looks like and contents of the pack

CRIXIVAN 400 mg hard capsules are supplied in HDPE bottles with a polypropylene cap and a foil 
seal containing 90 or 180 capsules. Not all pack sizes may be marketed.

The capsules are semi-translucent white and coded ‘CRIXIVAN 400 mg’ on them in green.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem,
The Netherlands

Manufacturer: Merck Sharp & Dohme B.V., Waarderweg 39, Postbus 581, 2003 PC Haarlem
The Netherlands

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


80

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България 
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland 
Merck Sharp & Dohme BV
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@ msd.no

Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
clic@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 29 00
msdromania@merck.com

 



81

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o.
Tel: + 386 1 5204 201
msd_slovenia@merck.com

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 800 00 673 (+357 22866700)
cyprus_info@merck.com 

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364224
msd_lv@merck.com.

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in 

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET