Tipranavir is a substrate, inducer and inhibitor of cytochrome P450 CYP3A. However, when combined with ritonavir at the recommended dose, the total inhibition of P450 CYP3A is noted.Joint use of tipranavir and a low dose of ritonavir with drugs, mainly metabolized with the participation of the CYP3A isoenzyme, can lead to a change in the concentration of tipranavir or other drugs in the plasma, which can affect their therapeutic and side effects.
Inhibitors of fusion
Enfuvirtide. Joint use of enfuvirtide with tipranavir and low dose of ritonavir was accompanied by an increase in the basal concentration of tipranavir during the steady state of pharmacokinetics by approximately 45%. A change in the dose of tipranavir or ritonavir is not required.
Didanosine. Tipranavir applied together with a low dose of ritonavir, leads to a decrease in the system exposure of didanosine.
The clinical significance of a decrease in the level of didanosine in plasma has not been established. To avoid incompatibility of dosage forms, the administration of didanosine in an enteric-soluble dosage form should be separated from the administration of tipranavir and ritonavir for at least 2 hours.
Altrenavir, atazanavir, lopinavir, saquinavir. Simultaneous use of tipranavir and a low dose of ritonavir with protease inhibitors amprenavir,atazanavir, lopinavir or saquinavir (each of which was used together with a low dose of ritonavir) led to a significant decrease in the concentration of protease inhibitors in plasma. The combination of the above protease inhibitors with tipranavir / ritonavir is not recommended.
Alfuzosin. The simultaneous use of tipranavir and alfuzosin leads to an increase in the concentration of alfuzosin and may cause hypotension.
Carbamazepine, phenobarbital and phenytoin Care should be taken in combination with tipranavir / ritonavir. Simultaneous use of carbamazepine 200 mg / day with tipranavir / ritonavir resulted in an increase in carbamazepine plasma concentration and a decrease in the minimum concentration of tipranavir, which may be the reason for the decrease in its effectiveness.
Salmeterol. The simultaneous use of tipranavir / ritonavir is not recommended. The combination of these drugs can increase the risk of unwanted cardiovascular reactions caused by salmeterol, including prolongation of the QT interval, palpitation and sinus tachycardia.
Rifabutin. Tipranavir (used together with a low dose of ritonavir) increases the concentration of rifabutin in the plasma by no more than 3 times, and the concentration of 25-O-deacetyl-rifabutin (active metabolite) is not more than 20-fold. Rifabutin increases the minimum concentration of tipranavir by 16%. It is recommended that the usual dose of rifabutin (300 mg per day) be reduced by at least 75% (eg 150 mg every other day or three times a week). Patients receiving rifabutin together with tipranavir / ritonavir, should be carefully monitored for possible adverse events associated with rifabutin therapy. It may be necessary to further reduce the dose.
Rifampicin (rifampin). The simultaneous use of tipranavir and rifampin (rifampin) is contraindicated. With the simultaneous use of protease inhibitors, including tipranavir with rifampicin (rifampia), a significant decrease in the concentrations of the protease inhibitor is expected. Decreased levels of tipranavir to suboptimal values may lead to a loss of virologic effect and to the development of virus resistance to tipranavir or to the whole group of protease inhibitors.
Tipranavir, used together with a low dose of ritonavir, reduces system exposure and the maximum concentration of ethinylestradiol by 150%, but does not significantly alter the pharmacokinetics of norethindrone. In the case of oral contraceptives, based on estrogens, alternative or additional contraceptive measures should be used in conjunction with tipranavir and ritonavir in a low dose. Patients using hormone replacement therapy should be observed to identify signs of estrogen deficiency. Women taking estrogens may have a higher risk of developing a rash that does not belong to the category of serious complications.
Tadalafil. Simultaneous use of tadalafil with tipranavir and ritonavir in a low dose even after the first administration of tipranavir / ritonavir resulted in an increase in the effect of tadalafil 2.3-fold, although there was no change in the effect of tadalafil during the steady state of pharmacokinetics of tipranavir / ritonavir. If tadalafil is used during the first dose of tipranavir / ritonavir, the use of tadalafil at the lowest dose is necessary.But after 7-10 days of taking tipranavir / ritonavir, when a stable state of the pharmaconetics of tipranavir and ritonavir is achieved, the dose of tadalafil may increase (if it is clinically necessary).
Sildenafil. A safe and effective dose of this drug in the case of joint use with tipranavir / ritonavir is not established. There is a possibility of undesirable reactions; caused by sildenafil (which include visual impairment, hypotension, priapism and fainting).
Omeprazole. Tipranavir, used in conjunction with a low dose of ritonavir, reduces system exposure and maximum concentrations of omeprazole by 71% and 73%, respectively. There are no significant clinical changes in the properties of tipranavir / ritonavir during the steady state of pharmacokinetics. When omeprazole is used in conjunction with tipranavir and ritonavir, an increase in the dose of omeprazole may be required.
Vegetable preparations containing St. John's wort extract are not to be used concomitantly with tipranavir and ritonavir. In the case of a combination of St. John's wort extract withprotease inhibitors, including those with tipranavir, a significant decrease in the concentration of the protease inhibitor is expected. A decrease in the level of tipranavir to suboptimal values may lead to a loss of virologic effect and to the development of virus resistance to tipranavir or to the whole group of protease inhibitors.
Bupropion. Tipranavir, used in conjunction with ritonavir in small doses, resulted in a steady state of pharmacokinetics in reducing the maximum concentration and systemic exposure of bupropion by approximately 50%. When using a combination of these three drugs, careful clinical monitoring is necessary.
Narcotic analgesics (methadone, meperidine). Joint use of tipranavir and a low dose of ritonavir with a single dose of methadone leads to a decrease in the maximum concentration of methadone by approximately 50%. Therefore, patients should be monitored for the development of the opiate withdrawal syndrome. An increase in the dose of methadone may be required. Expected that tipranavir in combination with a low dose of ritonavir will lead to a decrease in the concentration of meperidine and an increase in the concentration of the metabolite of normeperidine.Increasing the dose and prolonged use of meperidine together with tipranavir and low dose of ritonavir are not recommended due to an increase in the concentration of metabolite of normeperidine, which has analgesic effect and stimulating effect on the CNS (including causing seizures).
Midazolam. The simultaneous use of midazolam for oral administration and tipranavir / ritonavir is contraindicated. Ritonavir is an active inhibitor of the CYP3A isoenzyme and therefore affects the pharmacokinetics of drugs metabolized with this isoenzyme. The concentration of midazolam applied once intravenously with tipranavir / ritonavir (during the steady state of pharmacokinetics) increased 2.8-fold. If tipranavir / ritonavir is used in conjunction with parenteral midazolam, careful monitoring of patients with respiratory depression and / or lengthening of sedation is necessary; a possible dose change should be taken into account.
Immunosuppressants (ciclosporin, tacrolimus, sirolimus). When using these drugs in conjunction with tipranavir / ritonavir, monitoring of the concentration of immunosuppressants is recommended.
Theophylline.Tipranavir / ritonavir may decrease the concentration of theophylline, which in turn may require an increase in the dose of theophylline.
Desipramine. Tipranavir, used with a low dose of ritonavir, can increase the concentration of desipramine. It is recommended to reduce the dose of desipramine and monitor its concentration.
Fluticasone propionate. In post-marketing studies, it was reported that when ritonavir was used in patients who received fluticasone propionate inhalation or intranasally, systemic effects of corticosteroids, including Cushing's syndrome and adrenal suppression, were noted. Therefore, the combined use of fluticasone propionate and tipranavir / ritonavir is not recommended unless the potential benefit to the patient exceeds the risk of systemic side effects of corticosteroids.
Trazodone. Simultaneous use of trazodone with tipranavir and a low dose of ritonavir can increase the concentration of trazodone in plasma. After simultaneous use of trazodone and ritonavir, side effects such as nausea, dizziness, hypotension and syncope were observed.If trazodone is used in combination with tipranavir / ritonavir, caution should be exercised and consider the possibility of using a lower dose of trazodone.