Tipranavir

Tipranavir is metabolised by the hepatic system. Liver impairment could therefore result in an increase of tipranavir exposure and a worsening of its safety profile. Therefore, tipranavir should be used with caution, and with increased monitoring frequency, in patients with mild hepatic impairment (Child-Pugh Class A).

Interaction – Geometric mean change (%):

Aluminium- and magnesium-based antacid QD:

• Tipranavir
  • C_max: ↓25%
  • AUC: ↓27%

Mechanism unknown.

Recommendations concerning co-administration: Dosing of tipranavir, co-administered with low dose ritonavir, with antacids should be separated by at least a two hours time interval.

Interaction – Geometric mean change (%):

Abacavir 300 mg BID (TPV/r 750/100 mg BID):

• Abacavir
  • C_max: ↓46%
  • AUC: ↓36%

The clinical relevance of this reduction has not been established, but may decrease the efficacy of abacavir. Mechanism unknown.

Recommendations concerning co-administration: The concomitant use of tipranavir, coadministered with low dose ritonavir, with abacavir is not recommended unless there are no other available NRTIs suitable for patient management. In such cases no dosage adjustment of abacavir can be recommended.

Interaction – Geometric mean change (%):

Amprenavir/ritonavir 600/100 mg BID:

• Amprenavir
  • C_max: ↓39%
  • AUC: ↓44%
  • C_min: ↓55%

The clinical relevance of this reduction in amprenavir concentrations has not been established. Mechanism unknown.

Recommendations concerning co-administration: The concomitant use of tipranavir, coadministered with low dose ritonavir, with amprenavir/ritonavir is not recommended. If the combination is nevertheless considered necessary, a monitoring of the plasma levels of amprenavir is strongly encouraged.

Interaction – Geometric mean change (%):

Atazanavir/ritonavir 300/100 mg QD (TPV/r 500/100 mg BID):

Recommendations concerning co-administration: The concomitant use of tipranavir, coadministered with low dose ritonavir, with atazanavir/ritonavir is not recommended. If the co-administration is nevertheless considered necessary, a close monitoring of the safety of tipranavir and a monitoring of plasma concentrations of atazanavir are strongly encouraged.

Interaction – Geometric mean change (%):

Atorvastatin 10 mg QD:

• Atorvastatin
  • C_max: ↑8.6 fold
  • AUC: ↑9.4 fold
  • C_min: ↑5.2 fold
• Tipranavir ↔

Inhibition of CYP3A4 by tipranavir/r.

Recommendations concerning co-administration: Co-administration of atorvastatin and tipranavir, co-administered with low dose ritonavir, is not recommended. Other HMG-CoA reductase inhibitors should be considered such as pravastatin, fluvastatin or rosuvastatin. In cases where co-administration is necessary, the dose of 10 mg atorvastatin daily should not be exceeded. It is recommended to start with the lowest dose and careful clinical monitoring is necessary.

Coadministration of boceprevir with tipranavir/ritonavir is not recommended.

In a pharmacokinetic study of healthy volunteers, boceprevir decreased the exposure of ritonavir, and some ritonavir-boosted protease inhibitors. Boceprevir exposure was reduced when co-administered with ritonavir-boosted lopinavir or ritonavir-boosted darunavir. These drug-drug interactions may reduce the effectiveness of HIV protease inhibitors and/or boceprevir when co-administered.

Co-administration of bosentan and tipranavir with low dose ritonavir is not recommended.

Based on theoretical considerations, bosentan concentrations may increase upon co-administration with tipranavir and low dose ritonavir. Inhibition of CYP3A4 by tipranavir/r.

Interaction – Geometric mean change (%):

• Buprenorphine ↔
• Norbuprenorphine
  • AUC: ↓79%
  • C_max: ↓80%
  • C_min: ↓80%

Recommendations concerning co-administration: Due to reduction in the levels of the active metabolite norbuprenorphine, co-administration of Aptivus, coadministered with low dose ritonavir, and buprenorphine/naloxone may result in decreased clinical efficacy of buprenorphine. Therefore, patients should be monitored for opiate withdrawal syndrome.

Interaction – Geometric mean change (%):

Bupropion 150 mg BID:

• Bupropion
  • C_max: ↓51%
  • AUC: ↓56%
• Tipranavir ↔

The reduction of bupropion plasma levels is likely due to induction of CYP2B6 and UGT activity by RTV.

Recommendations concerning co-administration: If the co-administration with bupropion is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended dosage, despite the observed induction.

Interaction – Geometric mean change (%):

Carbamazepine 200 mg BID:

• Carbamazepine total*
  • C_max: ↑13%
  • AUC: ↑16%
  • C_min: ↑23%

* Carbamazepine total = total of carbamazepine and epoxy-carbamazepine (both are pharmacologically active moieties).

The increase in carbamazepine total PK parameters is not expected to have clinical consequences.

• Tipranavir C_min: ↓61% (compared to historical data)

The decrease in tipranavir concentrations may result in decreased effectiveness.

Carbamazepine induces CYP3A4.

Recommendations concerning co-administration: Carbamazepine should be used with caution in combination with tipranavir, co-administered with low dose ritonavir. Higher doses of carbamazepine (>200 mg) may result in even larger decreases in tipranavir plasma concentrations.

More frequent concentration monitoring of these medicinal products is recommended until blood levels have been stabilised.

Concentrations of cyclosporin, tacrolimus, or sirolimus cannot be predicted when co-administered with tipranavir co-administered with low dose ritonavir, due to conflicting effect of tipranavir, coadministered with low dose ritonavir, on CYP3A and P-gp.

Interaction – Geometric mean change (%):

Clarithromycin 500 mg BID:

CYP3A4 inhibition by tipranavir/r and P-gp (an intestinal efflux transporter) inhibition by clarithromycin.

Recommendations concerning co-administration: Whilst the changes in clarithromycin parameters are not considered clinically relevant, the reduction in the 14-OH metabolite AUC should be considered for the treatment of infections caused by Haemophilus influenzae in which the 14-OH metabolite is most active. The increase of tipranavir C_min may be clinically relevant. Patients using clarithromycin at doses higher than 500 mg twice daily should be carefully monitored for signs of toxicity of clarithromycin and tipranavir. For patients with renal impairment dose reduction of clarithromycin should be considered (see clarithromycin and ritonavir product information).

Tipranavir/ritonavir should not be administered concomitantly with cobicistat or cobicistat-containing products.

When co-administered, tipranavir and cobicistat exposures are markedly lower compared to that of tipranavir when boosted with low dose ritonavir.

A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with tipranavir/ritonavir is required. In patients with renal or hepatic impairment, co-administration of colchicine in patients on tipranavir/ritonavir is contraindicated.

Based on theoretical considerations, colchicine concentrations may increase upon co-administration with tipranavir and low dose ritonavir, due to tipranavir/ritonavir CYP3A and P-gp inhibition. However a decrease of colchicine concentrations cannot be excluded since both tipranavir and ritonavir exhibit inducing potential towards CYP3A and P-gp. Colchicine is a substrate of CYP3A4 and P-gp (an intestinal efflux transporter).

Dosage reduction and concentration monitoring of desipramine is recommended.

Tipranavir, co-administered with low dose ritonavir, is expected to increase desipramine concentrations Inhibition of CYP2D6 by tipranavir/r.

Interaction – Geometric mean change (%):

The clinical relevance of this reduction in didanosine concentrations has not been established. Mechanism unknown.

Recommendations concerning co-administration: Dosing of enteric-coated didanosine and Aptivus soft capsules, co-administered with low dose ritonavir, should be separated by at least 2 hours to avoid formulation incompatibility.

Interaction – Geometric mean change (%):

Transient inhibition of P-gp by tipranavir/r, followed by induction of P-gp by tipranavir/r at steadystate.

Recommendations concerning co-administration: Monitoring of digoxin serum concentrations is recommended until steady state has been obtained.

No dosage adjustment necessary in patients with normal renal function. In case of concomitant administration of emtricitabine and tipranavir/ritonavir, renal function should be evaluated before initiating the co-administration.

Potential interactions with renal transporters cannot be fully excluded

The clinical impact of the observed data, especially regarding the tipranavir with ritonavir safety profile, remains unknown. Nevertheless, the clinical data available from the RESIST trials did not suggest any significant alteration of the tipranavir with ritonavir safety profile when combined with enfuvirtide as compared to patients treated with tipranavir with ritonavir without enfuvirtide.

In studies where tipranavir coadministered with low-dose ritonavir was used with or without enfuvirtide, it has been observed that the steady-state plasma tipranavir trough concentration of patients receiving enfuvirtide were 45% higher as compared to patients not receiving enfuvirtide. No information is available for the parameters AUC and C_max. A pharmacokinetic interaction is mechanistically unexpected and the interaction has not been confirmed in a controlled interaction study.

Interaction – Geometric mean change (%):

Ethinyl oestradiol 0.035 mg/Norethindrone 1.0 mg QD (TPV/r 750/200 mg BID):

• Ethinyl oestradiol
  • C_max: ↓52%
  • AUC: ↓43%

Mechanism unknown.

• Norethindrone
  • C_max: ↔
  • AUC: ↑27%
• Tipranavir ↔

Recommendations concerning co-administration: The concomitant administration with tipranavir, co-administered with low dose ritonavir, is not recommended. Alternative or additional contraceptive measures are to be used when oestrogen based oral contraceptives are coadministered with tipranavir and low dose ritonavir. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.

Interaction – Geometric mean change (%):

• Etravirine
  • C_max: ↓71%
  • AUC: ↓76%
  • C_min: ↓82%

Concomitant use of tipranavir/ritonavir caused a decrease of etravirine exposure that could significantly impair the virologic response to etravirine.

Recommendations concerning co-administration: Co-administration of etravirine and tipranavir/ritonavir is not recommended.

Interaction – Geometric mean change (%):

Fluconazole 200 mg QD (Day 1) then 100 mg QD:

• Fluconazole ↔
• Tipranavir
  • C_max: ↑32%
  • AUC: ↑50%
  • C_min: ↑69%

Mechanism unknown.

Recommendations concerning co-administration: No dosage adjustments are recommended. Fluconazole doses >200 mg/day are not recommended.

Concomitant administration of tipranavir, co-administered with low dose ritonavir, and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period. The effects of high fluticasone systemic exposure on ritonavir plasma levels are as yet unknown.

In a clinical study where ritonavir 100 mg capsules bid were coadministered with 50 µg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82-89%). Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide. It is unknown whether the combination of tipranavir with ritonavir might cause a larger increase in fluticasone exposure.

Due to their metabolic profile and inherent risk of inducing torsades de pointes, administration of halofantrine and lumefantrine with tipranavir, co-administered with low dose ritonavir, is not recommended.

Based on theoretical considerations, tipranavir, co-administered with low dose ritonavir, is expected to increase halofantrine and lumefantrine concentrations. Inhibition of CYP3A4 by tipranavir/r.

Itraconazole or ketoconazole should be used with caution (doses >200 mg/day are not recommended).

Based on theoretical considerations tipranavir, co-administered with low dose ritonavir, is expected to increase itraconazole or ketoconazole concentrations. Based on theoretical considerations, tipranavir or ritonavir concentrations might increase upon co-administration with itraconazole or ketoconazole.

The combined use of tipranavir, coadministered with low dose ritonavir, with proton pump inhibitors is not recommended. If the coadministration is judged unavoidable, this should be done under close clinical monitoring.

Based on the metabolic profiles of tipranavir/r and the proton pump inhibitors, an interaction can be expected. As a result of CYP3A4 inhibition and CYP2C19 induction by tipranavir/r, lansoprazole and pantoprazole plasma concentrations are difficult to predict. Rabeprazole plasma concentrations might decrease as a result of induction of CYP2C19 by tipranavir/r.

Interaction – Geometric mean change (%):

Loperamide 16 mg QD:

Recommendations concerning co-administration: A pharmacodynamic interaction study in healthy volunteers demonstrated that administration of loperamide and tipranavir, coadministered with low dose ritonavir, does not cause any clinically relevant change in the respiratory response to carbon dioxide. The clinical relevance of the reduced loperamide plasma concentration is unknown.

Interaction – Geometric mean change (%):

Lopinavir/ritonavir 400/100 mg BID:

• Lopinavir
  • C_max: ↓47%
  • AUC: ↓55%
  • C_min: ↓70%

The clinical relevance of this reduction in lopinavir concentrations has not been established. Mechanism unknown.

Recommendations concerning co-administration: The concomitant use of tipranavir, coadministered with low dose ritonavir, with lopinavir/ritonavir is not recommended. If the combination is nevertheless considered necessary, a monitoring of the plasma levels of lopinavir is strongly encouraged.

Interaction – Geometric mean change (%):

Methadone 5 mg QD:

Mechanism unknown.

Recommendations concerning co-administration: Patients should be monitored for opiate withdrawal syndrome. Dosage of methadone may need to be increased.

Interaction – Geometric mean change (%):

• Omeprazole
  • C_max: ↓73%
  • AUC: ↓70%

Similar effects were observed for the S-enantiomer, esomeprazole.

Induction of CYP 2C19 by tipranavir/r.

• Tipranavir ↔

Recommendations concerning co-administration: The combined use of tipranavir, coadministered with low dose ritonavir, with either omeprazole or esomeprazole is not recommended. If unavoidable, upward dose adjustments for either omeprazole or esomeprazole may be considered based on clinical response to therapy. There are no data available indicating that omeprazole or esomeprazole dose adjustments will overcome the observed pharmacokinetic interaction. Recommendations for maximal doses of omeprazole or esomeprazole are found in the corresponding product information. No tipranavir with ritonavir dose adjustment is required.

Dosage increase and long-term use of meperidine with tipranavir, coadministered with low dose ritonavir, are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g. seizures).

Tipranavir, co-administered with low dose ritonavir, is expected to decrease meperidine concentrations and increase normeperidine metabolite concentrations.

Phenobarbital and phenytoin should be used with caution in combination with tipranavir, co-administered with low dose ritonavir.

Phenobarbital and phenytoin induce CYP3A4.

Co-administration of tipranavir, coadministered with low dose ritonavir, and pravastatin should be initiated with the lowest dose (10 mg/day) of pravastatin, titrated to treatment response, and accompanied with careful clinical monitoring for pravastatin associated symptoms as described in the label of pravastatin.

Based on similarities in the elimination between pravastatin and rosuvastatin, TPV/r could increase the plasma levels of pravastatin. Mechanism unknown.

Interaction – Geometric mean change (%):

Rifabutin 150 mg QD:

Inhibition of CYP3A4 by tipranavir/r.

No clinically significant change is observed in tipranavir PK parameters.

Recommendations concerning co-administration: Dosage reductions of rifabutin by at least 75% of the usual 300 mg/day are recommended (ie 150 mg on alternate days, or three times per week). Patients receiving rifabutin with tipranavir, co-administered with low dose ritonavir, should be closely monitored for emergence of adverse events associated with rifabutin therapy. Further dosage reduction may be necessary.

Close monitoring for signs of rilpivirine toxicity and possibly also dose adjustment of rilpivirine is recommended when coadministered with tipranavir/ritonavir.

Concomitant use of rilpivirine with some ritonavir-boosted protease inhibitors has demonstrated an increase in the plasma concentrations of rilpivirine.

Interaction – Geometric mean change (%):

Rosuvastatin 10 mg QD:

• Rosuvastatin
  • C_max: ↑123%
  • AUC: ↑37%
  • C_min: ↑6%
• Tipranavir ↔

Mechanism unknown.

Recommendations concerning co-administration: Co-administration of tipranavir, coadministered with low dose ritonavir, and rosuvastatin should be initiated with the lowest dose (5 mg/day) of rosuvastatin, titrated to treatment response, and accompanied with careful clinical monitoring for rosuvastatin associated symptoms as described in the label of rosuvastatin.

Concurrent administration of tipranavir, co-administered with low dose ritonavir, is not recommended.

The concurrent administration of tipranavir and low dose ritonavir may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. Inhibition of CYP3A4 by tipranavir/r.

Interaction – Geometric mean change (%):

Saquinavir/ritonavir 600/100 mg QD:

• Saquinavir
  • C_max: ↓70%
  • AUC: ↓76%
  • C_min: ↓82%

The clinical relevance of this reduction in saquinavir concentrations has not been established. Mechanism unknown.

Recommendations concerning co-administration: The concomitant use of tipranavir, coadministered with low dose ritonavir, with saquinavir/ritonavir is not recommended. If the combination is nevertheless considered necessary, a monitoring of the plasma levels of saquinavir is strongly encouraged.

Particular caution should be used when prescribing the phosphodiesterase (PDE5) inhibitors sildenafil or vardenafil in patients receiving tipranavir, coadministered with low dose ritonavir. A safe and effective dose has not been established when used with tipranavir, co-administered with low dose ritonavir. There is increased potential for PDE5 inhibitorassociated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). Co-administration of tipranavir/ritonavir with sildenafil, when used to treat pulmonary arterial hypertension, is contraindicated.

Co-administration of tipranavir and low dose ritonavir with PDE5 inhibitors is expected to substantially increase PDE5 concentrations and may result in an increase in PDE5 inhibitorassociated adverse events including hypotension, visual changes and priapism. CYP3A4 inhibition by tipranavir/r.

Interaction – Geometric mean change (%):

Tadalafil 10 mg QD:

No clinically significant change is observed in tipranavir PK parameters.

Recommendations concerning co-administration: It is recommended to prescribe tadalafil after at least 7 days of tipranavir with ritonavir dosing. A safe and effective dose has not been established when used with tipranavir, co-administered with low dose ritonavir. There is increased potential for PDE5 inhibitorassociated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).

Coadministration of telaprevir with tipranavir/ritonavir is not recommended.

Telaprevir is metabolized in the liver by CYP3A and is a P-glycoprotein (P-gp) substrate, but other enzymes may be involved in the metabolism. When tipranavir/ritonavir is co-administered with telaprevir, a decrease or an increase of telaprevir exposure could be expected. There is a heterogeneous effect of telaprevir on ritonavir-boosted protease inhibitor drug plasma levels, depending on the protease inhibitors. Therefore, a modification of tipranavir exposure cannot be ruled out.

Theophylline plasma concentrations should be monitored during the first two weeks of co-administration with tipranavir, co-administered with low dose ritonavir, and the theophylline dose should be increased as needed.

Based on data from the cocktail study where caffeine (CYP1A2 substrate) AUC was reduced by 43%, tipranavir with ritonavir is expected to decrease theophylline concentrations. Induction of CYP1A2 by tipranavir/r.

Co-administration is not recommended.

Based on theoretical considerations, tipranavir, co-administered with low dose ritonavir, is expected to increase tolterodine concentrations. Inhibition of CYP3A4 and CYP2D6 by tipranavir/r.

The combination should be used with caution and a lower dose of trazodone should be considered.

In a pharmacokinetic study performed in healthy volunteers, concomitant use of low dose ritonavir (200 mg twice daily) with a single dose of trazodone led to an increased plasma concentration of trazodone (AUC increased by 2.4 fold). Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir in this study. However, it is unknown whether the combination of tipranavir with ritonavir might cause a larger increase in trazodone exposure.

Based on the known interaction of voriconazole with low dose ritonavir, the co-administration of tipranavir/r and voriconazole should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Due to multiple CYP isoenzyme systems involved in voriconazole metabolism, it is difficult to predict the interaction with tipranavir, coadministered with low-dose ritonavir.

Interaction – Geometric mean change (%):

Warfarin 10 mg QD:

Inhibition of CYP2C9 with firstdose tipranavir/r, then induction of CYP2C9 with steady-state tipranavir/r.

Recommendations concerning co-administration: Tipranavir, co-administered with low dose ritonavir, when combined with warfarin may be associated with changes in INR (International Normalised Ratio) values, and may affect anticoagulation (thrombogenic effect) or increase the risk of bleeding. Close clinical and biological (INR measurement) monitoring is recommended when warfarin and tipranavir are combined.

Interaction – Geometric mean change (%):

Zidovudine 300 mg BID (TPV/r 750/100 mg BID):

• Zidovudine
  • C_max: ↓49%
  • AUC: ↓36%

The clinical relevance of this reduction has not been established, but may decrease the efficacy of zidovudine. Mechanism unknown.

Recommendations concerning co-administration: The concomitant use of tipranavir, coadministered with low dose ritonavir with zidovudine is not recommended unless there are no other available NRTIs suitable for patient management. In such cases no dosage adjustment of zidovudine can be recommended.

RESIST participants receiving tipranavir with ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters. The significance of this finding is being further monitored.

Fatal and non-fatal intracranial haemorrhages (ICH) have been reported in patients receiving tipranavir, many of whom had other medical conditions or were receiving concomitant medicinal products that may have caused or contributed to these events. However, in some cases the role of tipranavir cannot be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on tipranavir.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the tipranavir clinical trials.

In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving tipranavir with ritonavir.

In rats, co-administration with vitamin E increased the bleeding effects of tipranavir.

Tipranavir, co-administered with low dose ritonavir, should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medicinal products known to increase the risk of bleeding such as antiplatelet agents and anticoagulants or who are taking supplemental vitamin E. Based on the limits of exposure available from observation in clinical trials, it is recommended not to co-administer to patients more than 1,200 IU vitamin E per day.

Although the aetiology 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.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination therapy and should be monitored according to standard practice. Tipranavir with ritonavir should be discontinued once signs of worsening liver function occur in patients with pre-existing liver disease.

Tipranavir co-administered with low dose ritonavir, has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medicinal products. Caution should be exercised when administering tipranavir to patients with liver enzyme abnormalities or with a history of hepatitis. Increased ALAT/ASAT monitoring should be considered in these patients.

Tipranavir therapy should not be initiated in patients with pre-treatment ASAT or ALAT greater than 5 times the Upper Limit Normal (ULN) until baseline ASAT/ALAT is stabilised at less than 5 x ULN, unless the potential benefit justifies the potential risk.

Tipranavir therapy should be discontinued in patients experiencing ASAT or ALAT elevations greater than 10 x ULN, or developing signs or symptoms of clinical hepatitis during therapy. If another cause is identified (eg acute hepatitis A, B or C virus, gallbladder disease, other medicinal products), then rechallenge with tipranavir may be considered when ASAT/ALAT have returned to the patient’s baseline levels.

Liver monitoring

Monitoring of hepatic tests should be done prior to initiation of therapy, after two, four and then every four weeks until 24 weeks, and then every eight to twelve weeks thereafter. Increased monitoring (i.e. prior to initiation of therapy, every two weeks during the first three months of treatment, then monthly until 48 weeks, and then every eight to twelve weeks thereafter) is warranted when tipranavir and low dose ritonavir are administered to patients with elevated ASAT and ALAT levels, mild hepatic impairment, chronic hepatitis B or C, or other underlying liver disease.

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. A higher increase of blood lipids were seen with tipranavir/ritonavir than with comparators (other protease inhibitors) in clinical trials. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Mild to moderate rashes including urticarial rash, maculopapular rash, and photosensitivity have been reported in subjects receiving tipranavir, co-administered with low dose ritonavir. At 48-weeks in Phase III trials, rash of various types was observed in 15.5% males and 20.5% females receiving tipranavir coadministered with low dose ritonavir. Additionally, in one interaction trial, in healthy female volunteers administered a single dose of ethinyl oestradiol followed by tipranavir co-administered with low dose ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women receiving tipranavir co-administered with low dose ritonavir. In the paediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was higher than in adult patients.

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 pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with tipranavir, co-administered with low dose ritonavir.

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.

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some patients additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

There are no adequate data from the use of tipranavir in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Tipranavir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue breast-feeding if they are receiving tipranavir.

Contraception in males and females

Tipranavir adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe method of contraception should be used during treatment.

Fertility

Clinical data on fertility are not available for tipranavir. Preclinical studies performed with tipranavir showed no adverse effect on fertility.

Dizziness, somnolence, and fatigue have been reported in some patients; therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue, dizziness, or somnolence they should avoid potentially hazardous tasks such as driving or operating machinery.

Summary of the safety profile

Amongst the most common adverse reactions reported for tipranavir were gastrointestinal complaints such as diarrhoea and nausea as well as hyperlipidaemia. The most serious adverse reactions include hepatic impairment and liver toxicity. Intracranial haemorrhage (ICH) was only observed in post marketing experience.

Tipranavir co-administered with low dose ritonavir, has been associated with reports of significant liver toxicity. In Phase III RESIST trials, the frequency of transaminase elevations was significantly increased in the tipranavir with ritonavir arm compared to the comparator arm. Close monitoring is therefore needed in patients treated with tipranavir, co-administered with low dose ritonavir.

Limited data are currently available for the use of tipranavir, co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C. Tipranavir should therefore be used with caution in patients co-infected with hepatitis B or C. Tipranavir should be used in this patient population only if the potential benefit outweighs the potential risk, and with increased clinical and laboratory monitoring.

Summary of adverse reactions

Assessment of adverse reactions from HIV-1 clinical study data is based on experience in all Phase II and III trials in adults treated with the 500 mg tipranavir with 200 mg ritonavir dose twice daily (n=1397) and are listed below by system organ class and frequency according to the following categories: 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).

Tabulated summary of adverse reactions associated with tipranavir based on clinical studies and postmarketing experience:

Blood and lymphatic system disorders

Uncommon: neutropenia, anaemia, thrombocytopenia

Immune system disorders

Uncommon: hypersensitivity

Metabolism and nutrition disorders

Common: hypertriglyceridaemia, hyperlipidaemia

Uncommon: anorexia, decreased appetite, weight decreased, hyperamylasaemia, hypercholesterolaemia, diabetes mellitus, hyperglycaemia

Rare: dehydration

Psychiatric disorders

Uncommon: insomnia, sleep disorder

Nervous system disorders

Common: headache

Uncommon: dizziness, neuropathy peripheral, somnolence

Rare: intracranial haemorrhage^*

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea

Gastrointestinal disorders

Very common: diarrhoea, nausea

Common: vomiting, flatulence, abdominal pain, abdominal distension, dyspepsia

Uncommon: gastrooesophageal reflux disease, pancreatitis

Rare: lipase increased

Hepatobiliary disorders

Uncommon: hepatic enzyme increased (ALAT, ASAT), cytolytic hepatitis, liver function test abnormal (ALAT, ASAT), hepatitis toxic

Rare: hepatic failure (including fatal outcome), hepatitis, hepatic steatosis, hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Common: rash

Uncommon: pruritus, exanthem

Musculoskeletal and connective tissue disorders

Uncommon: myalgia, muscle spasms

Renal and urinary disorders

Uncommon: renal failure

General disorders and administration site conditions

Common: fatigue

Uncomm: pyrexia, influenza like illness, malaise

* see section Description of selected adverse reactions “Bleeding” for source of information

Description of selected adverse reactions

The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were seen at higher frequency among tipranavir with ritonavir treated patients when compared with the comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with ritonavir administration. The clinical significance of these observations has not been fully explored.

Hepatotoxicity

After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/or ASAT abnormalities was higher in tipranavir with ritonavir patients compared with comparator arm patients (10% and 3.4%, respectively). Multivariate analyses showed that baseline ALAT or ASAT above DAIDS Grade 1 and co-infection with hepatitis B or C were risk factors for these elevations. Most patients were able to continue treatment with tipranavir with ritonavir.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy

Hyperlipidaemia

Grade 3 or 4 elevations of triglycerides occurred more frequently in the tipranavir with ritonavir arm compared with the comparator arm. At 48 weeks these rates were 25.2% of patients in the tipranavir with ritonavir arm and 15.6% in the comparator arm.

Bleeding

This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials (n=6300). RESIST participants receiving tipranavir with ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters. The significance of this finding is being further monitored.

Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving tipranavir, many of whom had other medical conditions or were receiving concomitant medicinal products that may have caused or contributed to these events. However, in some cases the role of tipranavir cannot be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on tipranavir. An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the tipranavir clinical trials.

Rash

An interaction study in women between tipranavir, co-administered with low dose ritonavir, and ethinyl oestradiol/norethindrone demonstrated a high frequency of non-serious rash. In the RESIST trials, the risk of rash was similar between tipranavir with ritonavir and comparator arms (16.3% vs. 12.5%, respectively). No cases of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis have been reported in the clinical development programme of tipranavir.

Laboratory abnormalities

Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of patients in the tipranavir with ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST2) after 48-weeks were increased ASAT (6.1%), increased ALAT (9.7%), increased amylase (6.0%), increased cholesterol (4.2%), increased triglycerides (24.9%), and decreased white blood cell count (5.7%).

Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis, have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.

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. Reactivation of herpes simplex and herpes zoster virus infections were observed in the RESIST trials.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.

Paediatric population

In an open-label, dose-finding study of tipranavir plus ritonavir (Trial 1182.14), 28 children who were 12 years of age or above received tipranavir capsules. In general, adverse reactions were similar to those seen in adults, with the exception of vomiting, rash and pyrexia, which were reported more frequently in children than in adults. The most frequently reported moderate or severe adverse reactions in the 48 week analyses are noted below.

Most frequently reported moderate or severe adverse reactions in paediatric patients aged 12 to 18 years who took tipranavir capsules (reported in 2 or more children, Trial 1182.14, week 48 analyses, Full Analysis Set):

¹ Includes abdominal pain (N=1) and dyspepsia (N=1).
² Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash papular, erythema, rash maculo-papular, rash pruritic, and urticaria