nitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Acute overdose with Myocet will worsen toxic side effects. Treatment of acute overdose should focus on supportive care for expected toxicity and may include hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: Antineoplastic agents, anthracyclines and related substances, ATC code: L01DB01
The active substance in Myocet is doxorubicin HCl. Doxorubicin may exert its antitumour and toxic effects by a number of mechanisms including inhibition of topoisomerase II, intercalation with DNA and RNA polymerases, free radical formation and membrane binding. Liposomal-encapsulated compared with conventional doxorubicin was not found more active in doxorubicin resistant cell lines in vitro. In animals, liposome-encapsulated doxorubicin reduced the distribution to heart and gastrointestinal mucosa compared with conventional doxorubicin, while antitumoural efficacy in experimental tumours was maintained.
Myocet (60 mg/m2) + CPA (600 mg/m2) was compared with conventional doxorubicin + CPA (at the same doses) and Myocet (75 mg/m2) + CPA (600 mg/m2) was compared to epirubicin + CPA (at the same doses). In a third trial, Myocet (75 mg/m2) monotherapy was compared with conventional doxorubicin monotherapy (at the same dose). Findings regarding response rate and progression-free survival are provided in Table 3.
Table 3
Antitumour efficacy summary for combination and single-agent studies
Myocet/CPA
(60/600 mg/m2)
(n=142)
Dox 60/CPA
(60/600 mg/m2)
(n=155)
Myocet/CPA
(75/600 mg/m2)
(n=80)
Epi/CPA
(75/600 mg/m2)
(n=80)
Myocet
(75 mg/m2)
(n=108)
Dox
(75 mg/m2)
(n=116)
Tumour response rate
43%
43%
46%
39%
26%
26%
Relative Risk
(95% C.I.)
1.01
(0.78-1.31)
1.19
(0.83-1.72)
1.00
(0.64-1.56)
Median PFS (months)a
5.1
5.5
7.7
5.6
2.9
3.2
Risk Ratio
(95% C.I.)
1.03
(0.80-1.34)
1.52
(1.06-2.20)
0.87
(0.66-1.16)
Abbreviations: PFS, progression-free survival; Dox, doxorubicin; Epi, epirubicin; Relative Risk, comparator taken as reference; Risk Ratio, Myocet taken as reference
a Secondary endpoint
5.2 Pharmacokinetic properties
The plasma pharmacokinetics for total doxorubicin in patients receiving Myocet shows a high degree of inter-patient variability. In general however, the plasma levels of total doxorubicin are substantially higher with Myocet than with conventional doxorubicin, while the data indicate that peak plasma levels of free (not liposome-encapsulated) doxorubicin are lower with Myocet than with conventional doxorubicin. Available pharmacokinetic data preclude conclusions regarding the relationship between plasma levels of total/free doxorubicin and its influence on the efficacy/safety of Myocet. The clearance of total doxorubicin was 5.1 ± 4.8 l/h and the volume of distribution at steady state (Vd) was 56.6 ± 61.5 l whereas after conventional doxorubicin, clearance and Vd were 46.7 ± 9.6 l/h and 1,451 ± 258 l, respectively. The major circulating me
