Top INDEX
• What is it : Moclobemide.

• What is Known: Is Rodent Virus Contamination .. a Hazard?

• Who makes it: Meda, Micro, Roche, Valeant, ..

• Side Effects : Moclobemide: Adverse clinical & Overdose.

• How is it Used: Moclobemide .. for a major depressive episode.

• The Politics : The Anti-Competitive Effects of Brand-Controlled "Pseudo-Generics".

  
  

  • References : Online articles, studies, reports.

  • -Focus-: Monographs on Toxins and Enhancers.

Description: Moclobemide. INDEX
https://en.wikipedia.org/wiki/Moclobemide

Moclobemide is a reversible MAO-A inhibitor showing antidepressant activity.

Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. Valproic acid (VPA) and carbamazepine (CBZ) have been found to interact with psychotropic medications of all classes and many other drugs; VPA acts as a broad-spectrum inhibitor, and CBZ as a potent inducer of a variety of drug-metabolizing enzymes.

In humans moclobemide is rapidly and almost completely absorbed and totally metabolised via the liver.
Peak plasma levels occur 0.3 to 2 hours after oral administration. The bioavailability increases during the first week of therapy from 60% to 80% and more. The elimination half-life is around 2 hours. ...

Moclobemide has good penetration across the blood brain barrier with peak plasma levels within the central nervous system occurring 2 hours after administration.

Serotonin or 5-HT
In the body, 5-HT is involved with blood pressure and gut control.
In the brain, it controls mood, emotions, sleep/wake, feeding, temperature regulation, etc.

Too much serotonin and you feel sick, less hungry, get headaches or migraines.
Too little and you feel depressed, drowsy etc.

How MOCLOBEMIDE works.
If too little serotonin or noradrenaline produces the symptoms of depression then correcting this could help to reduce the symptoms.
One way of doing this is to stop the breakdown of transmitters. This is just what moclobemide does. It blocks the monoamine oxidase enzyme which breaks down the transmitter, so the next time an impulse comes along, there is more transmitter, a stronger message is passed, and activity in that part of the brain is increased.

Moclobemide is a benzamide, derivative of morpholine, which acts pharmacologically as a selective, reversible inhibitor of monoamine oxidase A (RIMA), a type of monoamine oxidase inhibitor (MAOI), and increases levels of norepinephrine (noradrenaline), dopamine, and especially serotonin in neuronal cells as well as in synaptic vesicles; extracellular levels also increase which results in increased monoamine receptor stimulation and suppression of REM sleep, down regulation of 3-adrenoceptors.

A single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B (MAO-B), blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. There is also some evidence pointing towards moclobemide possessing neuroprotective properties. There is no cumulative effect of moclobemide centrally when taken long-term. With long-term use of moclobemide, there is a significant down-regulation of B-adrenoceptors. Single or repeated dosing with 100-300 mg of moclobemide leads to a reduction in deaminated metabolites of amines such as 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethylglycol as well as 5-HIAA. Excretion of homovanillic acid and vanillylmandelic acid via urine is also reduced. There is also a temporary increase in prolactin during initial intake of 100-300 mg of moclobemide. L-dihydroxyphenylalanine is also reduced.

It is not approved for use in the United States, but is approved in other Western countries such as the UK and Australia (TGA approved in December 2000). It is produced by affiliates of the Hoffmann-La Roche pharmaceutical company. Initially, Aurorix was also marketed by Roche in South Africa, but was withdrawn after its patent rights expired and Cipla Medpro's Depnil and Pharma Dynamic's Clorix became available at half the cost.

No significant rise in blood pressure occurs when moclobemide is combined with amines such as tyramine-containing foods or pressor amine drugs, unlike with the older nonselective and irreversible monoamine oxidase inhibitors (MAOIs), which cause a severe rise in blood pressure with such combination. Due to the lack of anticholinergic, cardiovascular, cognitive and psychomotor impairments moclobemide is advantageous in the elderly as well as those with cardiovascular disease.

Reversible selective MAOIs such as moclobemide are widely underprescribed due to the misconception that the side effect profile of moclobemide is analogous to that of the irreversible and non-selective MAOIs. MAOIs such as moclobemide are reported to have a relatively fast onset of action compared to other antidepressant drug classes, and have good long-term tolerability in terms of side effects.

Tolerance does not seem to occur; research has found that moclobemide retains its beneficial therapeutic properties in depression for at least a year.

A concern of antidepressant adverse effects is sexual dysfunction; however, moclobemide has actually been found to increase the libido and also improve impaired erection, ejaculation and orgasm. Cardiovascular toxicity is a concern with antidepressants such as tricyclic antidepressants as well as the irreversible MAOIs; when cardiovascular toxicity is a concern, SSRIs or the reversible MAOIs such as moclobemide are an option as they lack or have a significantly reduced level of cardiovascular toxicity in terms of adverse effect as well as in overdose.

Moclobemide has been reported to be effective in the treament of migraine and chronic tension headache.
Menopausal flushing may also respond to moclobemide. Moclobemide may also have benefit for some patients with Parkinson's Disease by extending and enhancing the effects of l-dopa. The doses of moclobemide in breast milk are very low (0.06% of moclobemide being recovered in breast milk) and therefore it has been concluded that moclobemide is unlikely to have any adverse effect on a suckling baby. Reversible MAOIs such as moclobemide may have advantages in the treatment of depression associated with Alzheimer's disease due to its effect on noradrenaline. Cognitive impairments have been found to improve in people with dementia when depression is treated with moclobemide.

The incidence of adverse events is not correlated with age; however, adverse events occur more often in females than in males.
Side effects of moclobemide are exceptionally low, with insomnia, headache and dizziness being the most commonly reported side effects in the initial stages of therapy with moclobemide. ... moclobemide has been found to improve cognition, especially memory.... Alcohol related cognitive impairments are also improved by moclobemide. Improvements in cognition also occur in young depressed people after 6 weeks of treatment.

Moclobemide, even at high doses of 600 mg, does not impair the ability to drive a motor vehicle.
... as well as not causing weight gain. Unlike the irreversible MAOIs there is no evidence of liver toxicity with moclobemide. Other side effects include, nausea, insomnia, tremor and lightheadedness; orthostatic hypotension is uncommon even among the elderly. Behavioural toxicity or other impairments relating to everyday living does not occur with moclobemide, except in doses of 400 mg or higher, peripheral reaction time may be impaired. Peripheral oedema has been associated with moclobemide.

Cimetidine, .. causes a significant rise in moclobemide levels and therefore if the combination is used, lower doses of moclobemide have been recommended. There is little increase in the effects of alcohol when combined with moclobemide and, in fact, moclobemide causes a reduction in alcohol-related impairments. Moclobemide also interacts with pethidine/meperidine, and dextropropoxyphene. Ephedrine in combination with moclobemide increases the risk of cardiovascular adverse effects. Moclobemide is also likely to interact with warfarin. The combination of moclobemide with prescription or over the counter sympathomimetic drugs is not recommended due to the potential of significant drug interactions.

The reversible binding to MAO-A by moclobemide allows amines such as tyramine to displace moclobemide from MAO-A allowing its metabolism and removing the risk of a hypertensive crisis that occurs with irreversible MAO inhibition. Of 2300 people in multiple clinical trials who were treated with moclobemide in doses up to 600 mg with no dietary restrictions, none experienced a tyramine-mediated hypertensive reaction. As the pressor effect of moclobemide is so low, dietary restrictions are not necessary in people eating a normal diet, in contrast to irreversible MAOIs. However, some rare cheeses that have a high tyramine level may possibly cause a pressor effect and require caution. The potentiation of the pressor effect of tyramine by moclobemide is only one seventh to one tenth of that of irreversible MAOIs. In order to minimize this potentiation, postprandial administration (taken after meals) of moclobemide is recommended.

Moclobemide suppresses the unstimulated release of certain proinflammatory cytokines which are believed to be involved in the pathophysiology of major depression and stimulates the release of anti-inflammatory cytokines. Long-term treatment with moclobemide leads to an increase in cyclic adenosine monophosphate (cAMP) binding to cAMP-dependent protein kinase (PKA).

In healthy people moclobemide has a relatively small suppressing effect on REM sleep; in contrast, depressed people who have been treated with moclobemide, progressively show improved sleep over a 4-week period, with an increase in stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. There have been conflicting findings with regard to moclobemide altering cortisol levels and whether moclobemide increases growth hormone levels. Testosterone levels increase significantly with long-term use of moclobemide in depressed males.

Moclobemide also has neuroprotective properties in its demonstrated anti-hypoxia or anti-ischemia effects ...

it has been reported to be a pure MAO-A inhibitor, blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. No reuptake inhibition of any of the neurotransmitters occurs. The pharmacodynamic action encompasses activation, elevation of mood, and improvement of symptoms like dysphoria, fatigue, and difficulties in concentration. The duration and quality of sleep may be improved. In the treatment of depression the antidepressant effect often becomes evident in the first week of therapy (earlier than typically noted with TCAs/SSRIs).

Despite its short half-life the pharmacodynamic action of a single dose persists for approximately 16 hours.
The drug is almost completely metabolized in the liver; ... Less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours. ... The unchanged drug (less than 1%) as well as the metabolites are excreted renally (in urine).

The main degradation pathway of moclobemide is oxidation.
About 44 percent of the drug is lost due to the first pass effect through the liver.
Age and renal function do not affect the pharmacokinetics of moclobemide. ...
Food slows the absorption but does not affect the bioavailability of moclobemide.

The discovery of moclobemide in 1972 in Switzerland, as an antidepressant came about after it was initially investigated as a possible lipid lowering drug or antibiotic; when tests failed to demonstrate any antibiotic or antilipaemic properties; it was then tested for anti-cholinergic properties to see if it was a possible antidepressant but these tests also proved negative, leading researchers to think it may, in fact, be an antipsychotic; finally its reversible MAO-A properties as well as its lack of tyramine pressor effect. Clinical trials were commenced for moclobemide's effectiveness in the treatment of depression. .. In 1992 moclobemide was launched onto the world markets. Moclobemide was the first reversible MAO-A inhibitor to be widely marketed; ....

Research: Is Rodent Virus Contamination of Monoclonal Antibody
Preparations for Use in Human Therapy a Hazard? INDEX
July, 1986, Philip Carthew, http://www.researchgate.net/profile/Philip_Carthew
Journal of General Virology (Impact Factor: 3.18).
07/1986; 67 ( Pt 6)(6):963-74. DOI: 10.1099/0022-1317-67-6-963
Source: PubMed http://www.ncbi.nlm.nih.gov/pubmed/3011978
ResearchGate
http://www.researchgate.net/journal/0022-1317_Journal_of_General_Virology

The authors of this publication are on ResearchGate and have made the full-text available on their profiles.

Possible Rodent Virus contaminants:

1. Sendai virus -- raised temperature, weakness, tremors and ataxia.
2. Rous sarcoma virus
3. mouse adenovirus
4. cytomegalovirus
5. Encephalomyocarditis virus of mice
6. Ectromelia, the poxvirus of mice
7. HI (Toolan) virus
8. sialodacryoadenitis coronavirus
9. Hantaan virus
10. rat coronaviruses
11. avian leukosis virus
12. group A rotaviruses -- gastroenteritis in humans
13. lymphocytic choriomeningitis virus
14. (GD VII)
15. Theiler's mouse encephalomyelitis virus
16. Kilham rat virus
17. Newcastle disease virus
18. pneumonia virus of mice
19. reovirus type 3
20. newborn mouse pneumonitis virus
21. mouse hepatitis virus
22. murine retroviruses
23. polyoma virus

Since the discovery of monoclonal antibodies (K6hler & Milstein, 1975) much attention has been devoted to the development of reagents which would be of use in the detection and treatment of diseases, such as cancer and graft-versus-host disease resulting from human bone marrow allografts. ...

As most large-scale productions of monoclonal antibodies are carried out using ascites preparations induced in either mice or rats, a question which needs careful consideration is whether rodent viruses which contaminate many colonies of laboratory animals and may contaminate hybridomas, will be present in such therapeutically used materials and, if so, whether they constitute an additional pathological threat to the patients undergoing therapy. This is of particular relevance in cases where immunosuppression is used in the treatment regime. ...

Over the years many results have been reported documenting the serological testing of rodent colonies in the U.S.A. (Parker et al., 1966; Trentin et al., 1966) and the U.K. (Carthew et al., 1978; Gannon & Carthew, 1980) for a wide variety of rodent viruses. It is clear from the serological screening of mice that has been done in the U.S.A. that antibodies to

• Sendai virus,
• mouse hepatitis virus,
• reovirus type 3,
• pneumonia virus of mice,
• Theiler's mouse encephalomyelitis virus (GD VII) and
• polyoma virus were particularly commonly detected, while
• mouse adenovirus and
• newborn mouse pneumonitis virus (K virus) were less so (Parker et al., 1966).

Monitoring of animal facilities in the U.K. showed a similar prevalence of
• Sendai virus,
• pneumonia virus of mice,
• mouse hepatitis virus (type 1) (Carthew, 1978),
• Kilham rat virus and the
• rat coronaviruses (Gannon & Carthew, 1980).

In addition to these general serological data, we must also consider the numerous individual reports of enzootic or epizootic outbreaks of rodent diseases which have been reported.

One virus in particular, lymphocytic choriomeningitis virus, has caused outbreaks of disease in humans which were attributed to contact with infected hamsters in the U.S.A. (Baum et al., 1966; Biggar et al., t977) and Germany (Ackermann, 1976).

Ectromelia virus (which is not zoonotic) has also caused severe outbreaks of nationwide disease in mice in the U.S.A. (Held, 1981) and the U.K. (Carthew et al., 1977). The outbreaks of ectromelia in the U.S.A. have been traced back to mice imported from Czechoslovakia (where it seems to be endemic in mouse colonies) which were brought into the U.S.A. via England (Whitney et al., 1981).

Sendai virus has caused many outbreaks of disease even in barrier-maintained mouse colonies (Bhatt & Jonas, 1974; Parker et al., 1964; Burek et al., 1977), although the disease can exist in a subclinical form with little evidence of illness (Fujiwara et al., 1976; Parker & Reynolds, 1968).

Mouse hepatitis virus has been well documented worldwide as causing severe outbreaks of hepatitis and enteritis (Gledhill et al., 1955 ; Rowe et al., 1963; Carthew, 1977; Broderson et al., 1976; Hierholzer et al., 1979; Ishida & Fujiwara, 1979).

The most commonly occurring virus of rats responsible for clinical disease (besides Sendal virus) is the sialodacryoadenitis coronavirus which causes outbreaks of mumps-like salivary gland swelling with porphyrin accumulation in the eyes due to damage of the Harderian gland (Jonas et al., 1969; Carthew & Slinger, 1981 ; Utsumi et al., 1978).

More disturbingly, Hantaan virus has been found to be the cause of serious outbreaks of human disease in Belgium (Desmyter et al., 1983) and the U.K. (Lloyd et al., 1984) where Hantaan virus-infected rats were the source of disease. Since these rats were used to propagate rat myeloma cell lines and prepare ascites, the contamination of both cells and ascites with Hantaan virus is a real possibility which is currently being investigated (G. Lloyd, personal communication).

Recently, a rotavirus-like agent has been isolated from suckling rats suffering from diarrhoea (Vonderfecht et al., 1984). This virus has been shown by serological testing and examination of the nucleic acid to be distinct from the well-characterized group of rotaviruses associated with diarrhoea in simian, bovine and murine species, referred to as group A rotaviruses, and is closely related to the porcine group B rotavirus (Chen et al., 1985). It has been shown also to cause gastroenteritis in humans and at least one such infection was caused by contact with rats experimentally infected with this virus (Eiden et al., 1985). Virus isolated from human cases was also found to cause diarrhoea in suckling rats after oral administration. It is also thought that the virus may be the same (inferred by a similar RNA migration pattern) as the virus responsible for an epidemic of gastroenteritis in China (Hung et al., 1984). The evidence would seem to suggest that this new rotavirus-like agent is a zoonotic virus.

Viruses which could possibly be present in ascites preparations of monoclonal antibodies.

... It might also be remembered that when athymic or nude mice or rats are used for hybridoma cell ascites production, many of the natural virus diseases are chronic infections in these immunoincompetent rodents. Sendai virus is persistent in both nude mice (Ward et al., 1976; Iwai et al., 1979) and nude rats (Carthew & Sparrow, 1980a) as is pneumonia virus of mice (Carthew & Sparrow, 1980b), mouse hepatitis virus (Ward et al., 1976; Tamura et al., 1977; Carthew, 1981) and routine cytomegalovirus (Carthew, 1982). The problems associated with these chronic viral infections in nudemiee can be overcome by the maintenance of such animals in isolators where they remain virus-free provided they were derived initially by hysterectomy or embryo transfer (Carthew et al., 1983, 1985).

Zoonoses and probable human viral pathogens.

... In summary, it can be said that there is no example of parainfluenza virus type 1 unequivocally isolated from man which has been shown to be serologically identical with Sendai virus and also pathogenic for rodents. Sendai virus has been found to be experimentally communicable to rhesus and cynomolgus monkeys after intranasal instillation. Although no clinical symptoms were observed the monkeys seroconverted, while after intracerebral injection of Sendai virus into monkeys, clinical symptoms of raised temperature, weakness, tremors and ataxia were noted. One monkey died after 12 days with extensive consolidation of the lungs, while another showed haemorrhagic pneumonia at autopsy (Jensen et al., 1955). Although Sendai virus was possibly not isolated from humans originally, and may not be naturally transmissible between mice and humans, there is no doubt that it is pathogenic for human cells (Northrop & Walker, 1965) and also in human organ cultures of the trachea (Tyrrell & Hoorn, 1965) and might therefore be considered a hazard in monoclonal antibody preparations used in humans especially where administration is by the intravenous route.

... both HI (Toolan) virus and Kilham rat virus replicate in human B lymphocytes in culture and might thus be considered as possible human pathogens (Bass & Hetrick, 1975). The intravenous administration of monoclonal antibodies contaminated with Kilham rat virus, which is particularly prevalent in rats (Gannon & Carthew, 1980) would allow this virus direct access to a susceptible cell type in humans. Also, the use of monoclonal antibodies contaminated with this virus for in vitro selective cytotoxicity to bone marrow cells could lead to attachment of virus to cells and replication once they are replaced in a patient under treatment. This could be particularly dangerous for patients who are immunocompromised by the nature of their existing condition, or where they are also under immunosuppression as part of their subsequent treatment regime.

Although there are no recorded cases of transmission of reovirus 3 from animal to man this virus is so ubiquitous that this has probably occurred without being noticed. The original isolation of reovirus 3 was from a human anal specimen (Rosen et al., 1960) and reovirus 3 has also been isolated from patients with Burkitt's lymphoma (Bell, 1967). Reovirus 3 has been shown to persistently infect human embryonic fibroblasts (Bell & Ross, 1966) and to replicate in monkey cells (Hsiung, 1958). Although the isolation of reovirus 3 from patients with Burkitt's lymphoma may be adventitious and not associated with any pathology or disease state, the possibility of persistent infection with this virus and its exacerbation by immunosuppression would make it an undesirable contaminant in therapeutic treatments.

Encephalomyocarditis virus of mice is said to be indistinguishable serologicaUy from the other strains of this virus (Columbia-SK, MM and Mengo) (Andrewes & Pereira, 1967). The virus, which can be routinely passaged in mice, was originally isolated from a chimpanzee (Helwig & Schmidt, 1945). It has also been isolated from man (Dick et al., 1948) and in a number of cases of patients with central nervous system disease, this virus was isolated (Warren, 1965). Wild rats are thought to be a possible reservoir for encephalomyocarditis virus as antibodies to it are common in their sera (Warren et al., 1949). The virus can be grown in a wide variety of embryonic cells including human and mouse (Andrewes & Pereira, 1967).

Ectromelia, the poxvirus of mice, has not been isolated from any other species; however, this virus replicates in a wide variety of tissue culture systems including chick, mouse and HeLa cells (Porterfield & Allison, 1960). For this reason, it might also be regarded as a possible human pathogen.

Mouse adenovirus has been tested and found not to replicate in primary monkey kidney cells, human embryonic skin or muscle cultures (Blackmore, undated); however, it has been shown to be adaptable to human synovial tissue (McCoy) cells (Sharon & Pollard, 1964). ...

Of particular concern are the xenotropic retroviruses.
These only infect foreign hosts and caused concern during human turnout xenograft work in nude mice (Weiss, 1980).
There are examples of this type of infection occurring with a xenotropic feline virus, which infected and replicated in a human rhabdomyosarcoma after passage in the brain of a foetal kitten (McAllister et al., 1972; Livingston & Todaro, 1973); as well as this, human tumour xenografts in mice have also been shown to acquire murine xenotropic virus infections (Todaro et al., 1973; Crawford et al., 1979).

If this is possible in human turnout xenografts there would also seem to be the possibility that a routine retrovirus introduced into humans (via ascites fluids or cell supernatants) could cause a similar problem. Further possible dangers associated with xenotropic retroviruses are the production of a variant or recombinant virus more oncogenic or pathogenic than the original (Huebner et al., 1979) or the enhanced expression of cellular oncogenes leading to neoplastic transformation, as occurs with the activation of the c-myc gene by avian leukosis virus (Hayward et al., 1981). For these reasons it would seem to be necessary to add the murine retroviruses to the list of possible human pathogens to be excluded from therapeutic immunoglobulin preparations. The available data on the pathogenicity for humans and primates and replication of viruses in human or primate ceil lines are summarized in Table 2. ...

Removal of contaminating rodent viruses
during fractionation of monoclonal antibodies.

One possible approach to the problem of viruses contaminating monoclonal antibody preparations is to use a purification procedure for the preparations which removes all of the viruses which may be present. The often used technique of salt precipitation of antibodies followed by filtration through a 0.22 gm filter would not be stringent enough to remove all viruses. Heat treatment has been recently used to inactivate human T cell leukaemia virus III in factor VIII derived from blood plasma, but because of the extreme stability of some rodent viruses to heat (see Table 1) this is not likely to be a useful general procedure. Chemical treatments such as altering the pH or inactivation using /~-propiolactone would also be unsuitable as these would have a detrimental effect on the immunoglobulins in the preparations.

Alternatives such as molecular sieving to separate high molecular weight viruses from immunoglobulins are another possibility, while affinity chromatography on columns of anti-rat or anti-mouse antibody would be perhaps the best approach. The efficiency of any such operation can be monitored in the same way as was the purification of Namalwa cell-induced human interferon (Finter & Fantes, 1980). In this case a range of marker viruses, Sendai, Newcastle disease virus and Rous sarcoma virus (along with other viruses and micro-organisms) were deliberately added to the preparations and then the product was assayed for their absence (or inactivation) at the end of the procedure. This 'spiking' proved that the purification scheme used was very successful at removing a whole range of possible contaminants from interferon preparations and has the added advantage of also eliminating other micro-organisms (outside of the scope of the present review) which might well be present and which might be taken into consideration.

A good separation technique such as affinity chromatography might also have the added advantage of rendering the need for costly routine screening of batches of antibody for all viruses not necessary, as only the 'spiking' markers would have to be tested for. This overcomes the one possible criticism of testing for known rodent viruses, which is 'what about the ones that haven't yet been discovered?'.

Manufacturers: Meda, Micro, Roche, Valeant, INDEX

Manufacturer: Micro Labs Limited
Morex 150 (Moclobemide 150mg), analogue of Manerix

Manufacturer: Meda Valeant Canada Inc
LINK 1: https://en.wikipedia.org/wiki/Valeant_Pharmaceuticals
LINK 2: https://en.wikipedia.org/wiki/Meda_AB
LINK 3: http://www.valeantcanada.com/

Manufacturer: Roche Pharmaceutical and Health Care Products.
Aurorex

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From its 2 employees, 5,000 square foot beginning, the company has grown to employ over 6,500 people in research, development, manufacturing and distribution facilities world-wide. The Canadian operations of the Apotex Group of Companies with 5,000 employees now occupy over 3.4 million square feet in Montreal, Richmond Hill, Toronto, Etobicoke, Mississauga, Brantford, Windsor, Winnipeg, London, Calgary and Vancouver. Apotex produces more than 300 generic pharmaceuticals in approximately 4,000 dosages and formats which, in Canada, are used to fill over 89 million prescriptions a year - the largest amount of any pharmaceutical company in this country.

Export markets represent an ever growing portion of the total sales.
Apotex has also established a presence through subsidiaries, joint ventures or licensing agreements in Australia, Belgium, Czech Republic, Mexico, Netherlands, New Zealand, Poland, and Turkey, to name just a few. Healthcare professionals around the world rely on Apotex for quality and value.

Although the company's own business is developing and manufacturing generic pharmaceuticals, the success of Apotex has enabled it to diversify into a number of other health-related areas. The Apotex Pharmaceutical Group of Companies also researches, develops, manufactures and distributes fine chemicals, non-prescription and private label medicines, and disposable plastics for medical use.

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Side Effects: Moclobemide. INDEX
http://www.mentalhealth.com/

The MAO inhibition of moclobemide lasts about 8-10 hours and wears off completely by 24 hours after dosing. The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOIs phenelzine and approximately equivalent to tranylcypromine and isocarboxazid.

Adverse Effects

Table I lists the adverse events reported during clinical trials in which 1922 patients were treated with 50 to 600 mg/day moclobemide for depressive illness. Limited experience in 60 patients treated with 601 to 750 mg/day of moclobemide suggests that the incidence of adverse reactions may increase at higher doses.

Table I
Clinical Adverse Events > 1%

 Moclobemide Placebo
Organ System (n=1922) (n=271)
--------------------------------------------------------------
CNS   headache,   pressure in head    11.1 
                  insomnia, sleep disturbances    7.3      4.8
                  dizziness                       5.1      8.1
                  tremor                          5.0      3.0
                  increased agitation             4.5      2.6
                  restlessness, nervousness       4.1      2.6
                  sleepiness, somnolence          3.7      5.5
                  tiredness, sedation             3.0      4.1
                  increased anxiety, acute        2.8      2.2
                  anxiety state
                  weakness or faintness           1.2      1.8

Gastrointestinal  nausea                          5.2      4.8
                  constipation                    3.9      3.3
                  gastrointestinal pain           2.3      2.6
                  epigastric discomfort
                  sickness                        1.9      1.1
                  diarrhea                        1.8      1.1
                  abdominal fullness              1.6      1.5
                  abdominal pain
                  vomiting                        1.6      0.4
 
Cardiovascular    tachycardia, palpitations       3.8      3.3
                  hypotension                     3.0      0.4
                  orthostatic, reactive           2.3      3.3
                  hypotension
 
Anticholinergic   dry mouth                       9.2     10.7 
Miscellaneous     sweating                        2.4      2.2
                  blurred vision                  1.8      1.1
                  increase/loss of appetite       1.3      1.8

Other clinical adverse events with an incidence of < 1% are as follows:

Psychiatric:
Difficulties falling asleep, nightmares/dreams, hallucinations, memory disturbances, confusion, disorientation, delusions, increased depression, excitation/irritability, hypomanic symptoms, aggressive behavior, apathy, tension.

Central and Peripheral Nervous System:
Migraine, extrapyramidal effects, tinnitus, paresthesia, dysarthria.

Gastrointestinal:
Heartburn, gastritis, meteorism, indigestion.

Cardiovascular:
Hypertension, bradycardia, extrasystoles, angina/chest pain, phlebitic symptoms.

Dermatological/Mucocutaneous:
Exanthema/rash, allergic skin reaction, itching, gingivitis, stomatitis, dry skin, conjunctivitis.

Genitourinary:
Disturbances of micturition (dysuria, polyuria, tenesmus) metrorrhagia, prolonged menstruation.

Miscellaneous:
General malaise, skeletal/muscular pain, altered taste sensations, hot flushes/cold sensation, photopsia, dyspnea.

Laboratory Abnormalities:
Laboratory examinations were performed in a total of 1401 patients during clinical trials with moclobemide. Reductions were observed in leucocyte, AST (SGOT) and ALT (SGPT) values, however, these reductions were not considered clinically relevant. No other laboratory abnormalities were noted.

Overdose

Symptoms:
Signs and symptoms of overdosage with moclobemide include

• nausea,
• drowsiness,
• mild disorientation,
• slurred speech,
• amnesia and
• reduced reflexes.

One patient remained stuporous for 36 hours following an overdose with 1550 mg moclobemide. All abnormal laboratory values and vital signs returned to within normal range 1 to 5 days after overdosage. No organ toxicity was reported.

Treatment:
The treatment of overdosage could consist of general supportive measures.
Gastric lavage or induction of emesis, activated charcoal and fluid control may be of benefit.

Abstract: Moclobemide versus fluoxetine for a major depressive episode. INDEX
https://www.ncbi.nlm.nih.gov/pubmed/7954484
Reynaert C1, Parent M, Mirel J, Janne P, Haazen L. --- 1994

The efficacy and tolerability of moclobemide (300-600 mg daily) and fluoxetine (20-40 mg daily) were compared in a 6-week, double-blind study of 65 inpatients and 34 outpatients suffering from major depressive episodes (DSM III-R). No statistically significant differences between the two treatment groups were noted regarding efficacy (HDRS, CGI) or safety (adverse events, laboratory examination, vital signs).

Moclobemide (300-600 mg daily) and fluoxetine (20-40 mg daily) would thus appear to be comparable both in antidepressant efficacy and tolerability. Doubling the low dosage in non-responders after 3 weeks resulted in a statistically significant improvement of CGI in the moclobemide group by comparison with the fluoxetine group at study end, suggesting that 600 mg moclobemide/day can still improve the patient's condition, while 40 mg fluoxetine/day does not.
Sexual dysfunction was reported in two patients taking fluoxetine.

PMID: 7617806 -- [PubMed - indexed for MEDLINE]

The Anti-Competitive Effects of Brand-Controlled "Pseudo-Generics" INDEX
in the Canadian Pharmaceutical Market, by Aidan Hollis, Univ of Calgary.
CANADIAN PUBLIC POLICY -- ANALYSE DE POLITIQUES, VOL . XXIX , NO . 1 2003

Brand-name pharmaceutical firms in Canada, upon the expiry of their patent, always license a "pseudo-generic" firm to compete directly against generic firms. This pseudo-generic is identical to the brand-name product, but is marketed as a generic, with the pseudo-generic firm receiving a distribution fee. This strategy deters entry into smaller drug markets, since the threat of pseudo-generic competition deters other generics from making the investment required to enter; and slows the process of entry by competing generic firms.

The issue of pseudo-generics is currently (2003) before the courts in Canada, with Apotex (Canada's largest generic manufacturer) alleging that pseudo-generics, by misrepresenting their origin, are committing an offence under the Competition Act. Apotex has also proposed in a submission to the Competition Bureau that the use of pseudo-generics is an abuse of dominant position under the Act.

(2003)
Prescription drug expenditures are growing and currently stand at around $13 billion in Canada.
Pharmaceuticals' share of health-care expenditures has also been increasing, and currently stands at around 15 percent of total expenses. Generic drugs are therapeutically equivalent to brand-name drugs, but differ in the non-medicinal ingredients of the drugs. Because generic drugs are typically priced between 20 percent and 90 percent of the originator drug's price, they create significant savings for private, corporate, and public consumers: in Canada the savings are estimated to be over $1 billion. In Canada in 1999, generics had 40.6 percent of prescriptions but only 16 percent of sales revenues at drug stores. ...

Consumers and even some pharmacy professionals do not know that pseudo-generics are in fact identical to the brand-name drug. Firms tend to keep the information concerning pseudo-generics relatively well hidden. ...

In the current Canadian regulatory environment, it typically takes between 3 and 6 years to develop and obtain regulatory approval for generic drugs. No drug can be sold in Canada without first obtaining a "Notice of Compliance" or NOC from Health Canada. ... (may take 3 years) ... In contrast, in order for a pseudo-generic to obtain an NOC, all that is required is a letter from the brand to the minister stating that the pseudo-generic is identical to the brand-name product. This process may take only days to complete, at no cost to the brand or pseudo-generic. Pseudo-generics sometimes obtain their NOC years in advance of when they actually enter the market, as the brand-name firm does not permit the pseudo-generic firm to sell the product until some other generic competitor has acquired an NOC.

... pseudo-generics, far from adding competition and lowering prices for consumers, are likely to increase prices of both generic and brand-name drugs in markets where they enter.

... remedies could be effected through a legislative change, or through a decision by the provincial formularies, which have authority over which drugs they will include in their benefits list. From the perspective of the formularies collectively, not listing pseudo-generics would be desirable, since the benefits of pseudo-generics are rather small compared to the costs of lost competition. However, without concerted action, no provincial formulary has a private incentive to take action to solve the pseudo-generic problem. This casts the onus for solving the problem on Health Canada, since it is federal regulations that create the opportunity for patent-holding firms to abuse the process of the Notice of Allegation to delay and then pre-empt generic entry.

NOTE: In conversations with pharmacists I found that some did not know that there was usually a generic identical to the brand-name product; and one individual in charge of drug purchasing for a major hospital in Canada did not know which firms marketed pseudo-generics. Ordinary consumers typically have no knowledge at all of pseudo-generics.

References: Online articles, studies, reports. INDEX

• Description: Moclobemide.
  https://en.wikipedia.org/wiki/Moclobemide

• Monograph: Moclobemide.
  http://www.mentalhealth.com/

• Abstract: Moclobemide versus fluoxetine for a major depressive episode.
  https://www.ncbi.nlm.nih.gov/pubmed/7954484
  Reynaert C1, Parent M, Mirel J, Janne P, Haazen L. --- 1994
  
  

• Old anti-depressant ... treating heart failure.
  http://www.asrn.org/journal-nursing/
  732-old-antidepressant-offers-promise-in-treating-heart-failure.html

• 2002 -- NCBI -- Drug firms hype disease as sales ploy ...
  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1122820/
  
  

• Risks of .
  http://www.lifescript.com/health/a-z.aspx?m=1

• Monotherapy vs Combined Therapy with other pharmaceuticals.
  http://www.jove.com/visualize/abstract/19076986/
  moclobemide-monotherapy-vs-combined-therapy-with-valproic-acid-or
  
  

• Apotex Fermentation.
  http://www.apoferm.com/

• Apotex Product# 2129272.
  http://www.apotex.com/nz/en/products/detail.asp?id=2129272
  
  

• Meda Valeant Canada Inc
  http://www.canada-companies-info.com/meda-valeant-pharma-canada-inc-ee72/

  Customer Support: (800) 321-4576
  Medical Information/Product Complaints/Adverse Events - (877) 361-2719
  Patient Assistance for Valeant Products - (866) 268-7325

  
  

• Drug firms hype disease as sales ploy, industry chief claims. 2002
  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1122820/

• Blood Brain Barrier (BBB) test setup.
  http://www.jove.com/video/51278/
  setting-up-an-vitro-model-rat-blood-brain-barrier-bbb-focus-on-bbb

• Non-Insured Health Benefits, First Nations and Inuit Health Branch.
  http://publications.gc.ca/collections/collection_2013/sc-hc/H36-2-2013-eng.pdf
  
  

• Canada Prescriptions Plus
  https://www.canadaprescriptionsplus.com/prescription_info_list.aspx?drugname=manerix

• Eurodrugstore
  http://www.eurodrugstore.eu/antidepressants__3__en/manerix__1668.html

• UK Drugs.com Prescriptions: Manerix, 150 mg, film-coated.
  http://www.drugs.com/uk/manerix-150mg-film-coated-tablets-leaflet.html
  
  

• 2014 Meda Sustainability Report.
  https://www.unglobalcompact.org/system/attachments/cop_2015/151941/
  original/Meda_Annual_Report_incl._Sustainability_Report_2014.pdf?1428652549
  Manerix, p68 of 138, Continuing production and sales.

• 2010-04-Patent: Monoamine reuptake inhibitors.
  http://www.google.com/patents/EP2419400A1?cl=en

• Patent:
  http://www.google.com/patents/WO2014123967A2?cl=en