CRIXIVAN® 200 mg hard capsules

CRIXIVAN® 400 mg hard capsules

CRIXIVAN 200 mg:

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

Excipient: Each 200 mg capsule contains 74.8 mg lactose.

CRIXIVAN 400 mg:

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

Excipient: Each 400 mg capsule contains 149.6 mg lactose.

For the full list of excipients, see section 6.1

Hard capsule.

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

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

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

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).

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.

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, alprazolam, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), pimozide, ergot derivatives, simvastatin or lovastatin (see section 4.4).

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

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

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

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

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 overtime 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 (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).

Acute haemolytic anaemia

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

Hyperglycaemia

New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been reported in patients receiving protease inhibitors (PIs). In some of these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with medicinal products that have been associated with the development of diabetes mellitus or hyperglycaemia.

Fat redistribution

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicinal product related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Liver disease

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

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

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

Immune Reactivation Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Patients with coexisting conditions

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with PIs. In some patients additional factor VIII was given. In more than a half of the reported cases, treatment with PIs was continued or re-introduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

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

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

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Lactose

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

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

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

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

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

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

Refer also to sections 4.2 and 4.3.

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

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

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”).

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

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.

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.

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 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 ( 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.

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (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 (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.

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 dialysable by peritoneal or haemodialysis.

Pharmacotherapeutic group: Antivirals for system 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 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 8100 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-randomised 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 %.

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 (C_max) 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: AUC_0-8h 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: AUC_0-12h 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 19 of the patients, with a median (range) indinavir AUC 0-12hr, C_max, and C_min of 25421 nM*h (21489-36236 nM*h), 5758 nM (5056-6742 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 AUC_0–8hr 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 AUC_0-8hr 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 (C_min) 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 C_max. 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: AUC_0–8hr 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.

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.

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.

Capsule content

- anhydrous lactose

- magnesium stearate

Capsule shell:

- gelatin

- titanium dioxide (E171)

CRIXIVAN 200 mg: printing ink: indigo carmine (E132).

CRIXIVAN 400 mg: printing ink: titanium dioxide (E171), indigo carmine (E132) and iron oxide (E172).

Not applicable.

CRIXIVAN 200 mg – 3 years

CRIXIVAN 400 mg – 3 years for HDPE bottles containing 90 and 180 hard capsules

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

CRIXIVAN 200 mg: HDPE bottles with a polypropylene cap and a foil induction cap containing 180, 270 or 360 capsules.

CRIXIVAN 400 mg: HDPE bottles with a polypropylene cap and a foil induction cap containing 90 or 180 capsules.

Not all pack sizes may be marketed.

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.

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

CRIXIVAN 200 mg

EU/1/96/024/001

EU/1/96/024/002

EU/1/96/024/003

CRIXIVAN 400 mg

EU/1/96/024/004

EU/1/96/024/005

Date of first authorisation: 04/October/1996

Date of latest renewal: 18/July/2011

February 2012

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

© Merck Sharp & Dohme Limited 2012. All rights reserved.

SPC.CRX.12.UK.3590_IB-088