Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Potential for Sativex to affect other drugs/medicines
In vitro, Sativex was observed to be a reversible inhibitor of CYP3A4, 1A2, 2B6, 2C9 and 2C19 at concentrations far in excess of those likely to be achieved clinically. In vitro investigations also demonstrated that Sativex had the potential for time dependent inhibition of CYP3A4 at clinically relevant concentrations. The rate of the inactivation of the CYP3A4 enzyme is expected to be rapid.
Co-administration of Sativex with other CYP3A4 substrates may result in an increase in plasma concentration of the concomitant drug. A review of the dosing regimen of such medication is advised.

An in vitro, CYP induction study data indicated that plasma concentrations of THC and CBD arising from clinical doses of Sativex, could be sufficient to cause induction of CYP1A2, 2B6 and CYP3A4 at the mRNA level. Co-administration of Sativex with other drugs that are metabolised through these cytochrome P-450 enzymes may accelerate the metabolism and reduce the activity of these other drugs such as coumarins, statins, beta-blockers and corticosteroids. When sensitive CYP substrates are co- administered with Sativex, review of their dosing regimen is advised.

UGT enzymes
In an in vitro study Sativex was found to inhibit the UGT enzymes UGT1A9 and UGT2B7 at concentrations that could be achieved in the clinic. Care should be taken when prescribing Sativex with concomitant medications which are solely metabolised by both or either of these UGTs (e.g.
Propofol and certain antivirals). Patients with genetic glucuronidation disorders (e.g. Gilbert's disease) may exhibit increased serum concentrations of bilirubin and must be treated with caution when Sativex is co-administered.

Potential for Sativex to affect other drugs/medicines
The two main components of Sativex, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are metabolised by the cytochrome P-450 enzyme system.

Cytochrome P-450 enzyme inhibition
Concomitant treatment with the CYP3A4 inhibitor ketoconazole produced an increase in Cmax and AUC of THC (1.2- and 1.8-fold, respectively), its primary metabolite (3- and 3.6-fold, respectively) and of CBD (2- and 2-fold, respectively). Therefore, if concomitant drug treatment with CYP3A4 inhibitors (e.g. itraconazole, ritonavir, clarithromycin) is started or stopped during treatment with Sativex, a new dose titration may be required (see section 4.2).

Concomitant treatment of Sativex (4 sprays) with the CYP2C9 inhibitor fluconazole (200 mg capsule) resulted in an increase in mean THC Cmax of 22 % and mean AUC of 32 %. Exposure to the metabolite 11-OH-THC also increased by approximately 2.1-fold and 2.5-fold for Cmax and AUC respectively, indicating that fluconazole may inhibit its subsequent metabolism. The Cmax of CBD also increased by approximately 40 % but there was no significant change in AUC. There was no significant change in exposure to 7-OH-CBD either although an increase in the minor circulating metabolite of CBD, 6-OH CBD was noted (by up to 2.2-fold based on Cmax and AUC) .The clinical relevance of this drug-drug interaction is not fully understood, however care should be taken when co- administering Sativex with potent CYP2C9 inhibitors as it may lead to an increase in exposure to THC, CBD and their metabolites.

Cytochrome P-450 enzyme induction
Following treatment with the CYP3A4 inducer rifampicin reductions in Cmax and AUC of THC (40% and 20% reduction, respectively), its primary metabolite (85% and 87% reduction, respectively) and CBD (50% and 60% reduction, respectively) were observed. Therefore, concomitant treatment with strong enzyme inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s Wort) should be avoided whenever possible. If deemed necessary, careful titration is recommended, notably within the two weeks following the stop of the inducer.
General
Care should be taken with hypnotics, sedatives and drugs with potential sedating effects as there may be an additive effect on sedation and muscle relaxing effects.

Although there has been no greater rate of adverse events in patients already taking anti-spasticity agents with Sativex, care should be taken when co-administering Sativex with such agents since a reduction in muscle tone and power may occur, leading to a greater risk of falls.

Sativex may interact with alcohol, affecting co-ordination, concentration and ability to respond quickly. In general, alcoholic beverages should be avoided whilst using Sativex, especially at the beginning of treatment or when changing dose. Patients should be advised that if they do drink alcohol while using Sativex the additive CNS effects may impair their ability to drive or use machines, and increase the risk of falls.

Hormonal contraceptives
Sativex has been observed to induce drug metabolizing enzymes and transporters in vitro.
Sativex may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add an additional second barrier method.