Indinavir

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. Patients with severe hepatic impairment have not been studied; therefore, no dosing recommendations can be made.

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.

Interaction:

Dihydropyridine e.g. felodipine, nifedipine, nicardipine:

↑ dihydropyridine calcium channel blocker concentration

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

Recommendations concerning co-administration: Caution is warranted and clinical monitoring of patients is recommended.

Interaction:

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

Amprenavir AUC: ↑90%

Indinavir: ↔

Recommendations concerning co-administration: The appropriate doses for this combination, with respect to efficacy and safety, have not been established.

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 indinavir have not been studied and co-administration of these medicinal products is not recommended due to risk of worsening of these adverse reactions.

Interaction:

↑ atorvastatin concentration

Atorvastatin is less dependent on CYP3A4 for metabolism than lovastatin or simvastatin.

Recommendations concerning co-administration: Use the lowest possible dose of atorvastatin with careful monitoring. Caution is advised.

Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with indinavir.

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.

Cyclosporine A levels require progressive dose adjustment using therapeutic medicinal product monitoring.

Cyclosporine A (CsA) levels markedly increase in patients on PIs, including indinavir.

Interaction:

Delavirdine 400 mg TID (Indinavir 600 mg TID):

Indinavir AUC: ↑53%
Indinavir C_min ↑298%

(Relative to Indinavir 800 mg TID alone)

Delavirdine 400 mg TID Indinavir 400 mg TID:

Indinavir AUC: ↔
Indinavir C_min: ↑118%

(Relative to Indinavir 800 mg TID alone)

Delavirdine: ↔

Interaction:

Recommendations concerning co-administration: Dose reduction of indinavir to 400-600 mg every 8 hours should be considered.

Interaction: Interaction not studied.

↑ dexamethasone exposure expected (CYP3A inhibition).
↓ indinavir plasma concentrations may be expected (CYP3A induction).

Recommendations concerning co-administration: Careful monitoring of therapeutic and adverse effects is recommended when dexamethasone is concomitantly administered with indinavir.

Indinavir and didanosine formulations containing buffer should be administered at least one hour apart on an empty stomach.

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.

Interaction:

Didanosine enteric-coated 400 mg SD (Indinavir 800 mg SD):

Indinavir: ↔

(Relative to Indinavir 800 mg SD alone)

Didanosine: ↔

Recommendations concerning co-administration: Can be administered without any restrictions with respect to time of administration or food.

Interaction:

Efavirenz 600 mg QD (Indinavir 1,000 mg TID):

Indinavir AUC: ↓46%
Indinavir C_min: ↓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.

Efavirenz 200 mg QD (Indinavir 800 mg TID):

Indinavir AUC: ↓31%
Indinavir C_min: ↓40%

Efavirenz AUC: ↔

Recommendations concerning co-administration: No specific dose recommendation can be given.

Interaction:

Itraconazole 200 mg BID (Indinavir 600 mg TID):

Indinavir AUC: ↔
Indinavir C_min: ↑49%

(Relative to Indinavir 800 mg TID alone)

Recommendations concerning co-administration: Dose reduction of indinavir to 600 mg every 8 hours is recommended with administering itraconazole concurrently.

Interaction:

Ketoconazole 400 mg QD (Indinavir 600 mg TID):

Indinavir AUC: ↓20%
Indinavir C_min: ↑29%

(Relative to Indinavir 800 mg TID alone)

Ketoconazole 400 mg QD (Indinavir 400 mg TID):

Indinavir AUC: ↓56%
Indinavir C_min: ↓27%

(Relative to Indinavir 800 mg TID alone)

Recommendations concerning co-administration: Dose reduction of indinavir to 600 mg every 8 hours should be considered.

Interaction:

Not studied, combined administrations are expected to significantly increase concentrations of midazolam, particularly when midazolam is given orally.

Midazolam is extensively metabolized by CYP3A4.

Recommendations concerning co-administration: Indinavir and oral midazolam should not be coadministered. Caution should be used with coadministration of indinavir and parenteral midazolam. If indinavir 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.

Interaction:

Nevirapine 200 mg BID (Indinavir 800 mg TID):

Indinavir AUC: ↓28%

Nevirapine: ↔ (CYP3A induction)

Recommendations concerning co-administration: A dose increase of indinavir to 1,000 mg every 8 hours should be considered if given with nevirapine.

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

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

Interaction:

Quinidine 200 mg SD (Indinavir 400 mg SD):

Indinavir AUC and C_min: ↔

(Relative to Indinavir 400 mg SD)

↑ Quinidine concentration expected (CYP3A4 inhibition by indinavir)

Recommendations concerning co-administration: Caution is warranted and therapeutic concentration monitoring is recommended for quinidine when coadministered with indinavir. The use of indinavir/ritonavir with quinidine is contraindicated.

Interaction:

Rifabutin 300 mg QD (Indinavir 800 mg TID):

Indinavir AUC: ↓34%
Indinavir C_min: ↓39%

(Relative to Indinavir 800 mg TID alone)

Rifabutin AUC: ↑173%
Rifabutin C_min: ↑244%

(Relative to rifabutin 300 mg QD alone)

Rifabutin 150 mg QD (Indinavir 800 mg TID):

Indinavir AUC: ↓32%
Indinavir C_min: ↓40%

(Relative to Indinavir 800 mg TID alone)

Rifabutin AUC*: ↑54%
Rifabutin C_min*: ↑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)

Recommendations concerning co-administration: Dose reduction of rifabutin and dose increase of indinavir 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.

Interaction:

Ritonavir 100 mg BID (Indinavir 800 mg BID):

Indinavir AUC_24hr: ↑178%
Indinavir C_min: ↑11-fold

(Relative to Indinavir 800 mg TID alone*)

Ritonavir AUC_24hr: ↑72%
Ritonavir C_min: ↑62%

Ritonavir 200 mg BID (Indinavir 800 mg BID):

Indinavir AUC_24hr: ↑266%
Indinavir C_min: ↑24-fold

(Relative to Indinavir 800 mg TID alone*)

Ritonavir AUC: ↑96%
Ritonavir C_min: ↑371%

Ritonavir 400 mg BID (Indinavir 800 mg BID):

Indinavir AUC_24hr: ↑220%
Indinavir C_min: ↑24-fold

(Relative to Indinavir 800 mg TID alone*)

Ritonavir AUC_24hr: ↔

Ritonavir 400 mg BID (Indinavir 400 mg BID):

Indinavir AUC_24hr: ↑68%
Indinavir C_min: ↑10-fold

(Relative to Indinavir 800 mg TID alone*)

Ritonavir AUC_24hr: ↔

Ritonavir 100 mg BID (Indinavir 400 mg BID):

Indinavir AUC and C_min: ↔ (Relative to Indinavir 800 mg TID alone*)

* historical controls

Recommendations concerning co-administration: The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Preliminary clinical data suggest that indinavir 400 mg in combination with ritonavir 100 mg, both administered orally twice daily, may be an alternative dosing regimen. A boosted dose of 800 mg indinavir/100 mg ritonavir twice daily results in increased risk of adverse events.

Interaction:

Interaction not studied.

Interaction study with Lopinavir/ritonavir + rosuvastatin:

Rosuvastatin AUC: ↑ 2.08-fold
Rosuvastatin C_max: ↑ 4.66-fold

(Mechanism unknown)

Recommendations concerning co-administration: Combination not recommended.

Interaction:

Saquinavir 600 mg SD (hard gel capsule formulation) (Indinavir 800 mg TID):

Saquinavir AUC: ↑50%
Saquinavir C_min: ↑190%

(Relative to saquinavir 600 mg SD (hard gel formulation) alone)

Saquinavir 800 mg SD (soft gel capsule formulation) (Indinavir 800 mg TID):

Saquinavir AUC: ↑620%
Saquinavir C_min: ↑450%

(Relative to saquinavir 800 mg SD (soft gel formulation) alone)

Saquinavir 1,200 mg SD (soft gel capsule formulation) (Indinavir 800 mg TID):

Saquinavir AUC: ↑360%
Saquinavir C_min: ↑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 AUC_8h during co–administration with saquinavir.

Recommendations concerning co-administration: The appropriate doses for this combination, with respect to efficacy and safety, have not been established.

Interaction:

Sildenafil 25 mg SD (Indinavir 800 mg TID):

Indinavir AUC: ↑11%

Sildenafil AUC ↑340%

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

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

Interaction:

Interaction not studied.

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

Recommendations concerning co-administration: Co-administration of indinavir with tadalafil is likely to result in an increase of tadalafil by competitive inhibition of metabolism.

Interaction:

Vardenafil 10 mg SD (Indinavir 800 mg TID):

Vardenafil AUC: ↑16-fold

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

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

Interaction:

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: ↔

Recommendations concerning co-administration: The clinical significance of this finding is unknown.

Dose adjustment of warfarin may be required.

Not studied, combined administration may result in increased warfarin levels.

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.

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.

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.

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.

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.

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.

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 indinavir; 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 (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.

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.

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.

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.

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.

It is recommended that HIVinfected women do not breastfeed 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 breastfeeding during treatment.

Fertility

There are no data available regarding potential effects of indinavir 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 indinavir in a pooled analysis of controlled clinical trials.

Clinical adverse reactions reported by the investigators as possibly, probably, or definitely related to indinavir in ≥5% of patients treated with indinavir monotherapy or in combination with NRTI (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 indinavir monotherapy or in combination with NRTI. This overall safety profile remained similar for 107 patients treated with indinavir monotherapy or in combination with NRTI 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 postmarketing use for indinavir monotherapy and/or indinavir 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.

Blood and lymphatic system disorders

Very common: increases in MCV, decreases in neutrophils

Not known*: increased spontaneous bleeding in patients with haemophilia, anemia including acute haemolytic anaemia, thrombocytopenia.

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: headache, dizziness

Common: insomnia, hypoaesthesia; paraesthesia

Not known*: oral paraesthesia.

Gastrointestinal disorders

Very common: nausea, vomiting, diarrhoea, dyspepsia

Common: flatulence, dry mouth, acid regurgitation

Not known*: hepatitis, including reports of hepatic failure, pancreatitis.

Hepato-biliary disorders

Very Common: isolated asymptomatic hyperbilirubinaemia, increased ALT and AST

Not known*: liver function abnormalities

Skin and subcutaneous tissue disorders

Very common: rash, dry skin

Common: pruritus

Not known*: rash including erythema multiforme and Stevens Johnson syndrome, hypersensitivity vasculitis, alopecia, hyperpigmentation, urticaria; ingrown toenails and/or paronychia.

Musculoskeletal and connective tissue disorders

Common: myalgia

Not known*: myositis, rhabdomyolysis, increased CPK, osteonecrosis, periarthritis.

Renal and urinary disorders

Very common: haematuria, proteinuria, crystalluria

Common: nephrolithiasis, dysuria.

Not known*: 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.

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.

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.

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 indinavir 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 indinavir alone or in combination with other antiretroviral agents. Most patients continued treatment with indinavir 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 indinavir. Asymptomatic pyuria of unknown etiology was noted in 10.9% (6/55) of paediatric patients who received indinavir. Some of these events were associated with mild elevation of serum creatinine.