|Department of Health|
|MEDICINES CONTROL AGENCY|
|Market Towers 1 Nine Elms Lane London SW8 5NQ|
|Telephone 0171-273 0600|
|Facsimile 0171- 273 0737||.OG 00/02|
|20 April 2000|
Dear Mr Medawar,
Thank you for your letter of 21 January about Citalopram (Cipramil). I am sorry that it has not been possible to send an earlier reply. You have asked if the MCA considers certain entries in the UK Citalopram data sheet/SPC to be satisfactory in comparison with prescribing information in the USA, and, if not, what action the MCA win take. We are currently in the process of updating the Cipramil SPC as part of an exercise involving all drugs of this class and the points you have raised about Citalopram are being taken forward in this context as outlined below. It will be some months, however, before the revised SPC is finalised. You may be interested to know that the cost to the Agency in undertaking the comparison of the UK pre clinical data against the FDA prescribing information was £245 but on this occasion the MCA did not propose invoking a charge for that work. We do, of course, reserve the right to consider a charge for any future requests made under the Code.
Our comments - using the same sequence of headings as in your letter - are:
"Citalopram has no......carcinogenic potential"
The original preclinical assessment for citalopram was considered by the CSM in January 1989. The original UK assessment report, the Company's written summary of the data and the original study reports have been considered again within the MCA alongside relevant USA prescribing information. The data held by the MCA shows that there was an increased incidence of small intestine carcinoma in the rat carcinogenicity study in the low- and mid-dose groups but not in the top dose group This small increase was not dose related. This pattern of incidence is not indicative of a carcinogenic effect. When considered together with the lack of carcinogenic effect in the mouse carcinogenicity study, the overall balance of evidence is that citalopram is not carcinogenic. The revised SPC is likely to advise that preclinical data reveal no special hazard for humans based on conventional studies of carcinogenic potential.
"Citalopram has no....mutagenic potential"
Citalopram was not mutagenic in the Ames test in the two bacterial strains referred to in the USA prescribing information. The revised SPC is likely to advise that preclinical data reveal no special hazard for humans based on conventional studies of genotoxicity.
"Animal studies have not shown any evidence of teratogenic potential and citalopram does not affect reproduction or perinatal conditions ... there is no reason to have special concerns ... in women of child-bearing potential" The original studies conducted were a rat fertility and reproductive performance study, two definitive and one dose range finding rat and one rabbit embryo/fetal development (previously referred to as teratogenicity) studies, and a rat peri/postnatal study. Citalopram was teratogenic in one of two rat embryo/fetal development studies but only at dose levels which were toxic to the dams. At toxic dose levels citalopram impaired post-implantation survival and growth of fetuses. Citalopram was not teratogenic in either rat study at non-maternally toxic dose levels. Citalopram was not teratogenic in the rabbit.
At the time of the assessment of the application, it was a generally accepted concept that adverse effects on reproduction, including fetal malformations and embryo/fetal mortality, may be a consequence of maternal toxicity per se. It was also generally accepted that a compound that produces developmental effects only at maternally toxic dose levels should not be considered a developmental hazard in humans unless human exposure occurs at, or near, the maternally toxic level. The USA Prescribing Information states that the adverse effects in the rat study occurred at a dose level of 112 mg/kg/day, which is approximately 18 times the maximum recommended human dose (MRHD) of 60 mg/day on a body surface area (mg/m2) basis. The same document also states that the developmental no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on mg/m2 basis. Citalopram caused transient developmental delays and growth retardation at the top dose level in a fertility and general reproductive toxicity and a peri-postnatal development study respectively. These effects were reversible and had recovered at the end of the testing period. The UK statement will be updated as part of the current updating of the SPC.
"Citalopram appears in milk in very low concentrations ... it is not known whether citalopram excreted in milk may affect the infant"
The pregnancy and lactation section is being updated to reflect that Citalopram is known to be excreted in breast milk, that its effects on the nursing infant have not been established and that, if treatment with Citalopram is considered necessary, discontinuation of breast feeding should be considered.
"8 [overdose] cases considered to be due to citalopram alone ... no case was fatal." Fatalities have been reported in relation to Citalopram alone. This section will be updated as part of the current exercise.
"Citalopram should be administered as a single oral dose of 20mg daily ... this may be increased to 60mg daily
In psychiatric disorders such as depression it is difficult to determine precisely the maximum effective dose. The methods used to assess response are relatively insensitive compared, for example, with testing an anti-hypertensive agent. The main consideration in cases like citalopram is whether the maximum recommended dose is safe. The trials tested doses up to 80mg and there was no evidence that 60 was unsafe. It is sensible therefore to take account of an individual's response to increasing dose as the UK data sheet recommends. In the case of citalopram to stop at 40 mg might deny to some individuals the benefits of the higher and safe dose.
"Adverse effects observed with citalopram are in general mild and transient. They are most prominent during the first one or two weeks of treatment and usually attenuate as the depressive state improves."
This statement is a brief and general description of adverse reactions to Citalopram which introduces the detailed information on specific adverse reactions presented in the tables in section 4.8 of the Cipramil SPC. Section 4.8 is being reviewed, however we are not aware of information which would warrant a change to this statement.
"In humans citalopram did not impair cognitive (intellectual) function and psychomotor performance and has no or minimal sedative properties"
Section 4.8 of the Cipramil SPC states that somnolence occurred at a rate of 17% in clinical trials, which is similar to the US product information. This seems to be inconsistent with the statement in section 5.1 of the SPC and will be addressed during the updating of the SPC.
"This absence of effects on receptors could explain why citalopram produces fewer of the traditional effects such as dry mouth."
This statement is made in the context of a comparison with tricyclic antidepressants and some other SSRIs. It is generally accepted that SSRIs such as citalopram cause fewer antimuscarinic side effects than tricyclic antidepressants and therefore this statement is not misleading. Section 4.8 of the SPC states that dry mouth occurred at a rate of 18% in clinical trials and this is broadly similar to the 20% figure quoted in the US product information.
I hope you will find this helpful. If you consider that your request has not been handled properly under the terms of the Code you may, as you know, ask for an internal MCA review or you can ask a Member of Parliament to make a complaint on your behalf to the Parliamentary Commissioner for Administration who may decide to conduct his own investigation.
|Head of Executive Support|
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