Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Telbivudine
A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see telbivudine SmPC). Moreover, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Therefore, the combination of PegIntron with telbivudine is contraindicated (see section 4.3).

Methadone
In patients with chronic hepatitis C that were on stable methadone maintenance therapy and naïve to peginterferon alfa-2b, addition of 1.5 microgram/kg/week of PegIntron subcutaneously for 4 weeks increased R-methadone AUC by approximately 15 % (95 % Cl for AUC ratio estimate 103 – 128 %).
The clinical significance of this finding is unknown; however, patients should be monitored for signs and symptoms of increased sedative effect, as well as respiratory depression. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.

Effect of Peginterferon alfa-2b on Co-administered Medicines

The potential interaction of peginterferon alfa-2b (PegIntron) on substrates of metabolic enzymes was evaluated in 3 multiple-dose clinical pharmacology studies. In these studies, the effects of multiple-dose regimens of peginterferon alfa-2b (PegIntron) were investigated in Hepatitis C subjects (1.5 mcg/week) or healthy subjects (1 mcg/week or 3 mcg/week) (Table 4). A clinically significant pharmacokinetic interaction was not observed between peginterferon alfa-2b (PegIntron) and tolbutamide, midazolam or dapsone; therefore, no dosing adjustment is necessary when peginterferon alfa-2b (PegIntron) is administered with medicines metabolized by CYP2C9, CYP3A4 and N-acetyltransferase. Concomitant administration of peginterferon alfa-2b (PegIntron) with caffeine or desipramine modestly increased the exposure of caffeine and desipramine. When patients are administered PegIntron with medications metabolized by CYP1A2 or CYP2D6, the extent of the decrease in cytochrome P 450 activity is unlikely to have a clinical impact, except with medicines which have a narrow therapeutic margin (Table 5).


Table 4           Effect of Peginterferon alfa-2b on Co-administered Medicines 
Co-administered                  Dose of                           Study Population    Geometric Mean Ratio Medicine                         peginterferon                                         (Ratio with/without alfa-2b                                               peginterferon alfa-2b) 
AUC            Cmax
(90% CI)       (90% CI)
Caffeine                         1.5 mcg/kg/week                   Chronic Hepatitis   1.39           1.02 (CYP1A2 substrate)               (4 weeks)                         C Subjects (N=22)   (1.27, 1.51)   (0.95, 1.09) 1 mcg/kg/week                     Healthy Subjects    1.18           1.12 (4 weeks)                         (N=24)              (1.07, 1.31)   (1.05, 1.19) 3 mcg/kg/week                     Healthy Subjects    1.36           1.16 (2 weeks)                         (N=13)              (1.25, 1.49)   (1.10, 1.24) Tolbutamide                      1.5 mcg/kg/week                   Chronic Hepatitis   1.1#           NA (CYP2C9 substrate)               (4 weeks)                         C Subjects (N=22)   (0.94, 1.28) 1 mcg/kg/week                     Healthy Subjects    0.90#          NA (4 weeks)                         (N=24)              (0.81, 1.00)
3 mcg/kg/week                     Healthy Subjects    0.95           0.99 (2 weeks)                         (N=13)              (0.89, 1.01)   (0.92, 1.07) Dextromethorphan                 1.5 mcg/kg/week                   Chronic Hepatitis   0.96##         NA hydrobromide                     (4 weeks)                         C Subjects (N=22)   (0.73, 1.26) (CYP2D6 and                      1 mcg/kg/week                     Healthy Subjects    2.03#          NA CYP3A substrate)                 (4 weeks)                         (N=24)              (1.55, 2.67) Desipramine                      3 mcg/kg/week                     Healthy Subjects    1.30           1.08 (CYP2D6 substrate)               (2 weeks)                         (N=13)              (1.18, 1.43)   (1.00, 1.16) Midazolam                        1.5 mcg/kg/week                   Chronic Hepatitis   1.07           1.12 (CYP3A4 substrate)               (4 weeks)                         C Subjects (N=24)   (0.91, 1.25)   (0.94, 1.33) 1 mcg/kg/week                     Healthy Subjects    1.07           1.33 (4 weeks)                         (N=24)              (0.99, 1.16)   (1.15, 1.53) 3 mcg/kg/week                     Healthy Subjects    1.18           1.24 (2 weeks)                         (N=13)              (1.06, 1.32)   (1.07, 1.43) Dapsone                          1.5 mcg/kg/week                   Chronic Hepatitis   1.05           1.03 (N-acetyltransferase             (4 weeks)                         C Subjects (N=24)   (1.02, 1.08)   (1.00, 1.06) substrate)
# Calculated from urine data collected over an interval of 48-hours
## Calculated from urine data collected over an interval of 24-hours

Table 5     Precautions for co-administration (PegIntron should be administered with care when co-administered with the following medicines)
Medicines              Signs, Symptoms, and Treatment          Mechanism and Risk Factors Theophylline           Co-administration of theophylline       Metabolism of theophylline is with the product (PegIntron) may        suppressed by inhibitory action of increase the blood concentrations of    the product (PegIntron) on theophylline. Careful                   CYP1A2.
co-administration of theophylline with the product (PegIntron) is recommended. Package inserts of theophylline should be referred to when co-administering with the product (PegIntron)
Thioridazine           Co-administration of thioridazine       Metabolism of thioridazine is with the product (PegIntron) may        suppressed by inhibitory action of increase the blood concentrations of    the product (PegIntron) on thioridazine. Careful                   CYP2D6.
co-administration of thioridazine with the product (PegIntron) is recommended. Package inserts of
thioridazine should be referred to when co-administering with the product (PegIntron)
Theophylline,              Elevation of blood concentrations            Metabolism of other medicines in Antipyrine,                of these medicines has been                  the liver may be suppressed.
Warfarin                   reported when administered in combination with other interferon preparations and therefore care should be taken.
Zidovudine                 When administered in combination             Mechanism of action is unknown, with other interferon preparations,          but it is considered that both suppressive effect on bone marrow            medicines have bone marrow function may be strengthened and             depressive effects.
aggravation of blood cell reduction such as white blood cells decreased may occur.
Immuno-suppressive         When administered in combination             It is considered that graft rejection therapy                    with other interferon preparations,          reactions may be induced.
effect of immunosuppressive therapy may be weakened in transplant (kidney, bone marrow,
etc.) patients.

No pharmacokinetic interactions were noted between PegIntron and ribavirin in a multiple-dose pharmacokinetic study.

HCV/HIV Co-infection
Nucleoside analogues
Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis.
Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see ribavirin Physician's Insert).
Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV, although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine- induced anaemia.