Oracap may be available in the countries listed below.
Ingredient matches for Oracap
Omeprazole
Omeprazole is reported as an ingredient of Oracap in the following countries:
- Vietnam
International Drug Name Search
Thursday, 29 September 2016
Wednesday, 28 September 2016
Chlo Tuss EX
Generic Name: chlophedianol and guaifenesin (KLOE fe DYE a nol and gwye FEN e sin)
Brand Names: Chlo Tuss EX
What is Chlo Tuss EX (chlophedianol and guaifenesin)?
Chlophedianol is a cough suppressant. It affects the signals in the brain that trigger cough reflex.
Guaifenesin is an expectorant. It helps loosen congestion in your chest and throat, making it easier to cough out through your mouth.
The combination of chlophedianol and guaifenesin is used to treat cough and chest congestion caused by the common cold or flu.
Chlophedianol and guaifenesin will not treat a cough that is caused by smoking, asthma, or emphysema.
Chlophedianol and guaifenesin may also be used for purposes not listed in this medication guide.
What is the most important information I should know about Chlo Tuss EX (chlophedianol and guaifenesin)?
Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not use cough or cold medicine if you have untreated or uncontrolled breathing disorder such as asthma, emphysema, or chronic bronchitis. Drink extra fluids to help loosen the congestion and lubricate your throat while you are taking this medication.
What should I discuss with my healthcare provider before taking Chlo Tuss EX (chlophedianol and guaifenesin)?
Do not use cough or cold medicine if you have untreated or uncontrolled diseases such as asthma, emphysema, or chronic bronchitis.
To make sure you can safely use this medicine, tell your doctor if you have a cough with mucus, or cough caused by emphysema or chronic bronchitis.
It is not known whether chlophedianol and guaifenesin will harm an unborn baby. Do not use cough or cold medicine without telling your doctor if you are pregnant or plan to become pregnant while using the medicine. Chlophedianol and guaifenesin may pass into breast milk and may harm a nursing baby. Do not use cough or cold medicine without telling your doctor if you are breast-feeding a baby.
How should I take Chlo Tuss EX (chlophedianol and guaifenesin)?
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Cough or cold medicine is usually taken only for a short time until your symptoms clear up.
Drink extra fluids to help loosen the congestion and lubricate your throat while you are taking this medication.
Do not take for longer than 7 days in a row. Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache or skin rash.
Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children.
Measure liquid medicine with a special dose measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose measuring device, ask your pharmacist for one.
If you need surgery or medical tests, tell the surgeon or doctor ahead of time if you have taken a cough or cold medicine within the past few days. Store at room temperature away from moisture and heat. Do not freeze.
What happens if I miss a dose?
Since cough or cold medicine is taken when needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.
What happens if I overdose?
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
Overdose symptoms may include severe forms of some of the side effects listed in this medication guide.
What should I avoid while taking Chlo Tuss EX (chlophedianol and guaifenesin)?
This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Drinking alcohol can increase certain side effects of chlophedianol and guaifenesin. Ask a doctor or pharmacist before using any other cold, allergy, or cough medicine. Antitussives and expectorants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antitussive or expectorant.
Chlo Tuss EX (chlophedianol and guaifenesin) side effects
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using chlophedianol and guaifenesin and call your doctor at once if you have a serious side effect such as:
fast, slow, or uneven heart rate;
severe dizziness or anxiety, feeling like you might pass out;
mood changes, hallucinations;
severe headache;
tremor, seizure (convulsions); or
fever.
Less serious side effects may include:
mild dizziness or drowsiness;
mild headache;
diarrhea, nausea, upset stomach;
sleep problems (insomnia); or
feeling nervous, restless, or anxious.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What other drugs will affect Chlo Tuss EX (chlophedianol and guaifenesin)?
Before using chlophedianol and guaifenesin, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by chlophedianol and guaifenesin.
There may be other drugs that can interact with chlophedianol and guaifenesin. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.
More Chlo Tuss EX resources
- Chlo Tuss EX Side Effects (in more detail)
- Chlo Tuss EX Use in Pregnancy & Breastfeeding
- Chlo Tuss EX Drug Interactions
- 0 Reviews · Be the first to review/rate this drug
- Chlo Tuss EX Liquid MedFacts Consumer Leaflet (Wolters Kluwer)
Where can I get more information?
- Your pharmacist can provide more information about chlophedianol and guaifenesin.
See also: Chlo Tuss EX side effects (in more detail)
Tuesday, 27 September 2016
Ondansétron Biogaran
Ondansétron Biogaran may be available in the countries listed below.
Ingredient matches for Ondansétron Biogaran
Ondansetron
Ondansetron is reported as an ingredient of Ondansétron Biogaran in the following countries:
- France
Ondansetron hydrochloride dihydrate (a derivative of Ondansetron) is reported as an ingredient of Ondansétron Biogaran in the following countries:
- France
International Drug Name Search
Crocin
Crocin may be available in the countries listed below.
Ingredient matches for Crocin
Paracetamol
Paracetamol is reported as an ingredient of Crocin in the following countries:
- India
- Philippines
International Drug Name Search
Trileptal 150 mg, 300 mg, 600 mg Film-coated tablets
1. Name Of The Medicinal Product
Trileptal® 150 mg Film-coated Tablets
Trileptal® 300 mg Film-coated Tablets
Trileptal® 600 mg Film-coated Tablets
Oxcarbazepine 150mg Film-coated Tablets
Oxcarbazepine 300mg Film-coated Tablets
Oxcarbazepine 600mg Film-coated Tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 150 mg, 300 mg or 600 mg oxcarbazepine.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablets.
150 mg: pale grey green, ovaloid tablets, scored on both sides. Embossed with T/D on one side and C/G on the other side.
300 mg: yellow, ovaloid tablets, scored on both sides. Embossed with TE/TE on one side and CG/CG on the other side.
600 mg: light pink, ovaloid tablets scored on both sides. Embossed with TF/TF on one side and CG/CG on the other side.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4. Clinical Particulars
4.1 Therapeutic Indications
Trileptal is indicated for the treatment of partial seizures with or without secondarily generalised tonic-clonic seizures.
Trileptal is indicated for use as monotherapy or adjunctive therapy in adults and in children of 6 years of age and above.
4.2 Posology And Method Of Administration
In mono- and adjunctive therapy, treatment with Trileptal is initiated with a clinically effective dose given in two divided doses. The dose may be increased depending on the clinical response of the patient. When other antiepileptic medicinal products are replaced by Trileptal, the dose of the concomitant antiepileptic medicinal product(s) should be reduced gradually on initiation of Trileptal therapy. In adjunctive therapy, as the total antiepileptic medicinal product load of the patient is increased, the dose of concomitant antiepileptic medicinal product(s) may need to be reduced and/or the Trileptal dose increased more slowly (see section 4.5).
Trileptal can be taken with or without food.
The following dosing recommendations apply to all patients, in the absence of impaired renal function (see section 5.2). Drug plasma level monitoring is not necessary to optimise Trileptal therapy.
The tablets are scored and can be broken in two halves in order to make it easier for the patient to swallow the tablet. However, the tablet cannot be divided into equal doses. For children, who cannot swallow tablets or where the required dose cannot be administered using tablets, a Trileptal oral suspension is available.
Adults
Monotherapy
Trileptal should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. If clinically indicated, the dose may be increased by a maximum of 600 mg/day increments at approximately weekly intervals from the starting dose to achieve the desired clinical response. Therapeutic effects are seen at doses between 600 mg/day and 2,400 mg/day.
Controlled monotherapy trials in patients not currently being treated with antiepileptic medicinal products showed 1,200 mg/day to be an effective dose; however, a dose of 2400 mg/day has been shown to be effective in more refractory patients converted from other antiepileptic medicinal products to Trileptal monotherapy.
In a controlled hospital setting, dose increases up to 2,400 mg/day have been achieved over 48 hours.
Adjunctive therapy
Trileptal should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. If clinically indicated, the dose may be increased by a maximum of 600 mg/day increments at approximately weekly intervals from the starting dose to achieve the desired clinical response. Therapeutic responses are seen at doses between 600 mg/day and 2,400 mg/day.
Daily doses from 600 to 2,400 mg/day have been shown to be effective in a controlled adjunctive therapy trial, although most patients were not able to tolerate the 2400 mg/day dose without reduction of concomitant antiepileptic medicinal products, mainly because of CNS-related adverse events. Daily doses above 2400 mg/day have not been studied systematically in clinical trials.
Elderly
Adjustment of the dose is recommended in the elderly with compromised renal function (see 'Patients with renal impairment'). For patients at risk of hyponatraemia see section 4.4.
Children
In mono- and adjunctive therapy, Trileptal should be initiated with a dose of 8-10 mg/kg/day given in 2 divided doses. In adjunctive therapy, therapeutic effects were seen at a median maintenance dose of approximately 30 mg/kg/day. If clinically indicated, the dose may be increased by a maximum of 10 mg/kg/day increments at approximately weekly intervals from the starting dose, to a maximum dose of 46 mg/kg/day, to achieve the desired clinical response (see section 5.2).
Trileptal is recommended for use in children of 6 years of age and above. Safety and efficacy have been evaluated in controlled clinical trials involving approximately 230 children aged less than 6 years (down to 1 month). Trileptal is not recommended in children aged less than 6 years since safety and efficacy have not been adequately demonstrated.
All the above dosing recommendations (adults, elderly and children) are based on the doses studied in clinical trials for all age groups. However, lower initiation doses may be considered where appropriate.
Patients with hepatic impairment
No dosage adjustment is required for patients with mild to moderate hepatic impairment. Trileptal has not been studied in patients with severe hepatic impairment, therefore, caution should be exercised when dosing severely impaired patients (see section 5.2).
Patients with renal impairment
In patients with impaired renal function (creatinine clearance less than 30 ml/min) Trileptal therapy should be initiated at half the usual starting dose (300 mg/day) and increased, in at least weekly intervals, to achieve the desired clinical response (see section 5.2).
Dose escalation in renally impaired patients may require more careful observation.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Hypersensitivity
Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been received in the post-marketing period. Cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of Trileptal. If a patient develops these reactions after treatment with Trileptal, the drug should be discontinued and an alternative treatment started.
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25-30 % of these patients may experience hypersensitivity reactions (e.g. severe skin reactions) with Trileptal (see section 4.8).
Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients without history of hypersensitivity to carbamazepine. Such reactions can affect the skin, liver, blood and lymphatic system or other organs, either individually or together in the context of a systemic reaction (see section 4.8). In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Trileptal should be withdrawn immediately.
Dermatological effects
Serious dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme, have been reported very rarely in association with Trileptal use. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and very rarely be fatal. Trileptal associated cases occurred in both children and adults. The median time to onset was 19 days. Several isolated cases of recurrence of the serious skin reaction when rechallenged with Trileptal were reported. Patients who develop a skin reaction with Trileptal should be promptly evaluated and Trileptal withdrawn immediately unless the rash is clearly not drug related. In case of treatment withdrawal, consideration should be given to replacing Trileptal with other antiepileptic drug therapy to avoid withdrawal seizures. Trileptal should not be restarted in patients who discontinued treatment due to a hypersensitivity reaction (see section 4.3).
Hyponatraemia
Serum sodium levels below 125 mmol/l, usually asymptomatic and not requiring adjustment of therapy, have been observed in up to 2.7 % of Trileptal treated patients. Experience from clinical trials shows that serum sodium levels returned towards normal when the Trileptal dosage was reduced, discontinued or the patient was treated conservatively (e.g. restricted fluid intake). In patients with pre-existing renal conditions associated with low sodium or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, desmopressin) as well as NSAIDs (e.g. indometacin), serum sodium levels should be measured prior to initiating therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then at monthly intervals for the first three months during therapy, or according to clinical need. These risk factors may apply especially to elderly patients. For patients on Trileptal therapy when starting on sodium-lowering medicinal products, the same approach for sodium checks should be followed. In general, if clinical symptoms suggestive of hyponatraemia occur on Trileptal therapy (see section 4.8), serum sodium measurement may be considered. Other patients may have serum sodium assessed as part of their routine laboratory studies.
All patients with cardiac insufficiency and secondary heart failure should have regular weight measurements to determine occurrence of fluid retention. In case of fluid retention or worsening of the cardiac condition, serum sodium should be checked. If hyponatraemia is observed, water restriction is an important counter-measurement. As oxcarbazepine may, very rarely, lead to impairment of cardiac conduction, patients with pre-existing conduction disturbances (e.g. atrioventricular-block, arrhythmia) should be followed carefully.
Hepatic function
Very rare cases of hepatitis have been reported, which in most of the cases resolved favourably. When a hepatic event is suspected, liver function should be evaluated and discontinuation of Trileptal should be considered.
Hematological effects
Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with Trileptal during post-marketing experience (see section 4.8). Discontinuation of the medicinal product should be considered if any evidence of significant bone marrow depression develops.
Suicidal behaviour
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for oxcarbazepine.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Hormonal contraceptives
Female patients of childbearing age should be warned that the concurrent use of Trileptal with hormonal contraceptives may render this type of contraceptive ineffective (see section 4.5). Additional non-hormonal forms of contraception are recommended when using Trileptal.
Alcohol
Caution should be exercised if alcohol is taken in combination with Trileptal therapy, due to a possible additive sedative effect.
Withdrawal
As with all antiepileptic medicinal products, Trileptal should be withdrawn gradually to minimise the potential of increased seizure frequency.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Enzyme induction
Oxcarbazepine and its pharmacologically active metabolite (the monohydroxy derivative, MHD) are weak inducers in vitro and in vivo of the cytochrome P450 enzymes CYP3A4 and CYP3A5 responsible for the metabolism of a very large number of drugs, for example, immunosuppressants (e.g. ciclosporin, tacrolimus), oral contraceptives (see below), and some other antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma concentration of these medicinal products (see table below summarizing results with other antiepileptic medicinal products).
In vitro, oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferases (effects on specific enzymes in this family are not known). Therefore, in vivo oxcarbazepine and MHD may have a small inducing effect on the metabolism of medicinal products which are mainly eliminated by conjugation through the UDP-glucuronyl transferases. When initiating treatment with Trileptal or changing the dose, it may take 2 to 3 weeks to reach the new level of induction.
In case of discontinuation of Trileptal therapy, a dose reduction of the concomitant medications may be necessary and should be decided upon by clinical and/or plasma level monitoring. The induction is likely to gradually decrease over 2 to 3 weeks after discontinuation.
Hormonal contraceptives: Trileptal was shown to have an influence on the two components, ethinylestradiol (EE) and levonorgestrel (LNG), of an oral contraceptive. The mean AUC values of EE and LNG were decreased by 48-52 % and 32-52% respectively. Therefore, concurrent use of Trileptal with hormonal contraceptives may render these contraceptives ineffective (see section 4.4). Another reliable contraceptive method should be used.
Enzyme inhibition
Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions could arise when co-administering high doses of Trileptal with medicinal products that are mainly metabolised by CYP2C19 (e.g. phenytoin). Phenytoin plasma levels increased by up to 40 % when Trileptal was given at doses above 1200 mg/day (see table below summarizing results with other anticonvulsants). In this case, a reduction of co-administered phenytoin may be required (see section 4.2).
Antiepileptic medicinal products
Potential interactions between Trileptal and other antiepileptic medicinal products were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarised in the following table.
Summary of antiepileptic medicinal product interactions with Trileptal
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Preliminary results indicate that oxcarbazepine may result in lower lamotrigine concentrations, possibly of importance in children, but the interaction potential of oxcarbazepine appears lower than seen with concomitant enzyme inducing drugs (carbamazepine, phenobarbitone, and phenytoin).
Strong inducers of cytochrome P450 enzymes (i.e. carbamazepine, phenytoin and phenobarbitone) have been shown to decrease the plasma levels of MHD (29-40 %) in adults; in children 4 to 12 years of age, MHD clearance increased by approximately 35% when given one of the three enzyme-inducing antiepileptic medicinal products compared to monotherapy. Concomitant therapy of Trileptal and lamotrigine has been associated with an increased risk of adverse events (nausea, somnolence, dizziness and headache). When one or several antiepileptic medicinal products are concurrently administered with Trileptal, a careful dose adjustment and/or plasma level monitoring may be considered on a case by case basis, notably in paediatric patients treated concomitantly with lamotrigine.
No autoinduction has been observed with Trileptal.
Other medicinal product interactions
Cimetidine, erythromycin, viloxazine, warfarin and dextropropoxyphene had no effect on the pharmacokinetics of MHD.
The interaction between oxcarbazepine and MAOIs is theoretically possible based on a structural relationship of oxcarbazepine to tricyclic antidepressants.
Patients on tricyclic antidepressant therapy were included in clinical trials and no clinically relevant interactions have been observed.
The combination of lithium and oxcarbazepine might cause enhanced neurotoxicity.
4.6 Pregnancy And Lactation
Pregnancy
Risk related to epilepsy and antiepileptic medicinal products in general:
It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3% in the general population. In the treated population, an increase in malformations has been noted with polytherapy, however, the extent to which the treatment and/or the illness is responsible has not been elucidated.
Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.
Risk related to oxcarbazepine:
Clinical data on exposure during pregnancy are still insufficient to assess the teratogenic potential of oxcarbazepine. In animal studies, increased embryo mortality, delayed growth and malformations were observed at maternally toxic dose levels (see section 5.3).
Taking these data into consideration:
• If women receiving Trileptal become pregnant or plan to become pregnant, the use of this product should be carefully re-evaluated. Minimum effective doses should be given, and monotherapy whenever possible should be preferred at least during the first three months of pregnancy.
• Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
• During pregnancy, an effective antiepileptic oxcarbazepine treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.
Monitoring and prevention:
Antiepileptic medicinal products may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. As the efficacy of this supplementation is not proved, a specific antenatal diagnosis can be offered even for women with a supplementary treatment of folic acid.
Data from a limited number of women indicate that plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that clinical response should be monitored carefully in women receiving Trileptal treatment during pregnancy to ensure that adequate seizure control is maintained. Determination of changes in MHD plasma concentrations should be considered. If dosages have been increased during pregnancy, postpartum MHD plasma levels may also be considered for monitoring.
In the newborn child:
Bleeding disorders in the newborn caused by antiepileptic agents have been reported. As a precaution, vitamin K1 should be administered as a preventive measure in the last few weeks of pregnancy and to the newborn.
Lactation
Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. The effects on the infant exposed to Trileptal by this route are unknown. Therefore, Trileptal should not be used during breast-feeding.
4.7 Effects On Ability To Drive And Use Machines
The use of Trileptal has been associated with adverse reactions such as dizziness or somnolence (see section 4.8). Therefore, patients should be advised that their physical and/ or mental abilities required for operating machinery or driving a car might be impaired.
4.8 Undesirable Effects
The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue occurring in more than 10% of patients.
The undesirable effect profile by body system is based on AEs from clinical trials assessed as related to Trileptal. In addition, clinically meaningful reports on adverse experiences from named patient programs and postmarketing experience were taken into account.
Frequency estimate* :- very common: 1/10; common: 1/100 - < 1/10; uncommon: 1/1,000 - < 1 /100; rare: 1/10,000 - < 1/1,000; very rare: < 1/10,000; unknown: cannot be estimated from the available data.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* according to CIOMS III frequency classification
†Very rarely clinically significant hyponatraemia (sodium <125 mmol/l) can develop during Trileptal use. It generally occurred during the first 3 months of treatment with Trileptal, although there were patients who first developed a serum sodium <125 mmol/l more than 1 year after initiation of therapy (see section 4.4).
4.9 Overdose
Isolated cases of overdose have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment. Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatraemia, ataxia and nystagmus. There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the medicinal product by gastric lavage and/or inactivation by administering activated charcoal should be considered.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antiepileptics
ATC code: N03A F 02
Pharmacodynamic effects
The pharmacological activity of oxcarbazepine is primarily exerted through the metabolite (MHD) (see section 5.2). The mechanism of action of oxcarbazepine and MHD is thought to be mainly based on blockade of voltage-sensitive sodium channels, thus resulting in stabilisation of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminishment of propagation of synaptic impulses. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may also contribute to the anticonvulsant effects. No significant interactions with brain neurotransmitter or modulator receptor sites were found.
Oxcarbazepine and its active metabolite (MHD), are potent and efficacious anticonvulsants in animals. They protected rodents against generalised tonic-clonic and, to a lesser degree, clonic seizures, and abolished or reduced the frequency of chronically recurring partial seizures in Rhesus monkeys with aluminum implants. No tolerance (i.e. attenuation of anticonvulsive activity) against tonic-clonic seizures was observed when mice and rats were treated daily for 5 days or 4 weeks, respectively, with oxcarbazepine or MHD.
5.2 Pharmacokinetic Properties
Absorption
Following oral administration of Trileptal, oxcarbazepine is completely absorbed and extensively metabolised to its pharmacologically active metabolite (MHD).
After single dose administration of 600 mg Trileptal to healthy male volunteers under fasted conditions, the mean Cmax value of MHD was 34 μmol/l, with a corresponding median tmax of 4.5 hours.
In a mass balance study in man, only 2 % of total radioactivity in plasma was due to unchanged oxcarbazepine, approximately 70 % was due to MHD, and the remainder attributable to minor secondary metabolites which were rapidly eliminated.
Food has no effect on the rate and extent of absorption of oxcarbazepine, therefore, Trileptal can be taken with or without food.
Distribution
The apparent volume of distribution of MHD is 49 litres.
Approximately 40 % of MHD, is bound to serum proteins, predominantly to albumin. Binding was independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.
Oxcarbazepine and MHD cross the placenta. Neonatal and maternal plasma MHD concentrations were similar in one case.
Biotransformation
Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of Trileptal. MHD is metabolised further by conjugation with glucuronic acid. Minor amounts (4 % of the dose) are oxidised to the pharmacologically inactive metabolite (10, 11-dihydroxy derivative, DHD).
Elimination
Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95 % of the dose appears in the urine, with less than 1 % as unchanged oxcarbazepine. Faecal excretion accounts for less than 4 % of the administered dose. Approximately 80 % of the dose is excreted in the urine either as glucuronides of MHD (49 %) or as unchanged MHD (27 %), whereas the inactive DHD accounts for approximately 3 % and conjugates of oxcarbazepine account for 13 % of the dose.
Oxcarbazepine is rapidly eliminated from the plasma with apparent half-life values between 1.3 and 2.3 hours. In contrast, the apparent plasma half-life of MHD averaged 9.3 ± 1.8 h..
Dose proportionality
Steady-state plasma concentrations of MHD are reached within 2 - 3 days in patients when Trileptal is given twice a day. At steady-state, the pharmacokinetics of MHD are linear and show dose proportionality across the dose range of 300 to 2,400 mg/day.
Special populations
Patients with hepatic impairment
The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900 mg oral dose. Mild to moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. Trileptal has not been studied in patients with severe hepatic impairment.
Patients with renal impairment
There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Trileptal is administered as a single 300 mg dose, in renally impaired patients (creatinine clearance < 30 mL/min) the elimination half-life of MHD is prolonged by 60-90 % (16 to 19 hours) with a two fold increase in AUC compared to adults with normal renal function (10 hours).
Children
The pharmacokinetics of Trileptal were evaluated in clinical trials in paediatric patients taking Trileptal in the dose range 10-60 mg/kg/day. Weight-adjusted MHD clearance deceases as age and weight increases approaching that of adults. The mean weight clearance in children 4 to 12 years of age is approximately 40% higher that that of adults. Therefore MHD exposure in these children is expected to be about two-thirds that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, weight-adjusted MHD clearance is expected to reach that of adults.
Pregnancy
Data from a limited number of women indicate that MHD plasma levels may gradually decrease throughout pregnancy (see section 4.6).
Elderly
Following administration of single (300 mg) and multiple doses (600 mg/day) of Trileptal in elderly volunteers (60 - 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30 % - 60 % higher than in younger volunteers (18 - 32 years of age). Comparisons of creatinine clearances in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. No special dose recommendations are necessary because therapeutic doses are individually adjusted.
Gender
No gender related pharmacokinetic differences have been observed in children, adults, or the elderly.
5.3 Preclinical Safety Data
Preclinical data indicated no special hazard for humans based on repeated dose toxicity, safety pharmacology and genotoxicity studies with oxcarbazepine and the pharmacologically active metabolite, monohydroxy derivative (MHD).
Evidence of nephrotoxicity was noted in repeated dose toxicity rat studies but not in dog or mice studies. As there are no reports of such changes in patients, the clinical relevance of this finding in rats remains unknown.
Immunostimulatory tests in mice showed that MHD (and to a lesser extent oxcarbazepine) can induce delayed hypersensitivity.
Animal studies revealed effects such as increases in the incidence of embryo mortality and some delay in antenatal and/or postnatal growth at maternally toxic dose levels. There was an increase in rat foetal malformations in one of the eight embryo toxicity studies, which were conducted with either oxcarbazepine or the pharmacologically active metabolite (MHD), at a dose which also showed maternal toxicity (see section 4.6).
In the carcinogenicity studies, liver (rats and mice), testicular and female genital tract granular cell (rats) tumours were induced in treated animals. The occurrence of liver tumours was most likely a consequence of the induction of hepatic microsomal enzymes; an inductive effect which, although it cannot be excluded, is weak or absent in patients treated with Trileptal. Testicular tumours may have been induced by elevated luteinizing hormone concentrations. Due to the absence of such an increase in humans, these tumours are considered to be of no clinical relevance. A dose-related increase in the incidence of granular cell tumours of the female genital tract (cervix and vagina) was noted in the rat carcinogenicity study with MHD. These effects occurred at exposure levels comparable with the anticipated clinical exposure. The mechanism for the development of these tumours has not been elucidated. Thus, the clinical relevance of these tumours is unknown.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet core:
silica, colloidal anhydrous
cellulose, microcrystalline
hypromellose
crospovidone
magnesium stearate.
Tablet coating:
hypromellose
talc
titanium dioxide (E 171).
150 mg coating only:
macrogol 4000
iron oxide, yellow (E 172)
iron oxide red (E 172)
iron oxide black (E 172).
300 mg tablet coating only:
macrogol 8000
iron oxide, yellow (E 172).
600 mg coating only:
macrogol 4000
iron oxide red (E 172)
iron oxide black (E 172).
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
6.5 Nature And Contents Of Container
Blister containing 10 tablets. Blister material: PVC/PE/PVDC with aluminium foil backing.
Tablets 150 mg: blister pack of 30, 50, 100, 200 and/or 500 tablets.
Tablets 300 mg: blister pack of 30, 50, 100, 200 and/or 500 tablets.
Tablets 600 mg: blister pack of 30, 50, 100, 200 and/or 500 tablets.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Autho
Citalopram Capsules
Dosage Form: capsules
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of citalopram or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Citalopram is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use)
Citalopram Capsules Description
Citalopram hydrobromide is an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant agents. Citalopram hydrobromide is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, HBr with the following structural formula:
The molecular formula is C20H22BrFN2O and its molecular weight is 405.35.
Citalopram hydrobromide occurs as a fine white to off-white powder. Citalopram hydrobromide is sparingly soluble in water and soluble in ethanol.
Citalopram hydrobromide 10 mg capsules have an ivory body and yellow cap and contain citalopram hydrobromide equivalent to 10 mg citalopram base. Citalopram hydrobromide 20 mg capsules have an ivory body and pink cap and contain citalopram hydrobromide equivalent to 20 mg citalopram base. Citalopram hydrobromide 40 mg capsules have an ivory body and a green cap and contain citalopram hydrobromide equivalent to 40 mg citalopram base. The capsules also contain the following inactive ingredients: corn starch, crospovidone, edible inks, gelatin, lactose monohydrate, magnesium stearate, titanium dioxide, and yellow iron oxide. The following coloring agents are used in the yellow (10 mg) capsules: D&C Red No. 28, D&C Yellow No. 10, and FD&C Yellow No. 6. The following coloring agents are used in the pink (20 mg) capsules: D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1, and FD&C Red No. 40. The following coloring agents are used in the green (40 mg) capsules: D&C Yellow No. 10 and FD&C Blue No. 1.
Citalopram Capsules - Clinical Pharmacology
Pharmacodynamics
The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14 day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer.
Citalopram has no or very low affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1-, α2-, and ß-adrenergic, histamine H1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs.
Pharmacokinetics
The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. The tablet and oral solution dosage forms of citalopram hydrobromide are bioequivalent.
Absorption and Distribution
Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%.
Metabolism and Elimination
Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance.
Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In humans, unchanged citalopram is the predominant compound in plasma. At steady state, the concentrations of citalopram's metabolites, DCT and DDCT, in plasma are approximately one-half and one-tenth, respectively, that of the parent drug. In vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram.
In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of citalopram.
Population Subgroups
Age - Citalopram pharmacokinetics in subjects ≥ 60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, citalopram AUC and half-life were increased in the elderly subjects by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg is the recommended dose for most elderly patients (see DOSAGE AND ADMINISTRATION).
Gender - In three pharmacokinetic studies (total N=32), citalopram AUC in women was one and a half to two times that in men. This difference was not observed in five other pharmacokinetic studies (total N=114). In clinical studies, no differences in steady state serum citalopram levels were seen between men (N=237) and women (N=388). There were no gender differences in the pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender is recommended.
Reduced hepatic function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 20 mg is the recommended dose for most hepatically impaired patients (see DOSAGE AND ADMINISTRATION).
Reduced renal function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of citalopram in patients with severely reduced renal function (creatinine clearance <20 mL/min).
Drug-Drug Interactions
In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited.
Since CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of 3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram. However, coadministration of citalopram and the potent 3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. Citalopram steady state levels were not significantly different in poor metabolizers and extensive 2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with citalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on citalopram metabolism. See Drug Interactions under PRECAUTIONS for more detailed information on available drug interaction data.
Clinical Efficacy Trials
The efficacy of citalopram as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18 to 66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram doses of 10, 20, 40, and 60 mg/day, showed that citalopram at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose.
In two long-term studies, depressed patients who had responded to citalopram during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20 to 60 mg/day in the second study) were randomized to continuation of citalopram or to placebo. In both studies, patients receiving continued citalopram treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg/day of citalopram.
Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
Comparison of Clinical Trial Results
Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.
Indications and Usage for Citalopram Capsules
Citalopram is indicated for the treatment of depression.
The efficacy of citalopram in the treatment of depression was established in 4 to 6 week, controlled trials of outpatients whose diagnosis corresponded most closely to the DSM-III and DSM-III-R category of major depressive disorder (see CLINICAL PHARMACOLOGY).
A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
The antidepressant action of citalopram in hospitalized depressed patients has not been adequately studied.
The efficacy of citalopram in maintaining an antidepressant response for up to 24 weeks following 6 to 8 weeks of acute treatment was demonstrated in two placebo-controlled trials (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use citalopram for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Contraindications
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
Citalopram is contraindicated in patients with a hypersensitivity to citalopram or any of the inactive ingredients in citalopram hydrobromide capsules.
Warnings
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
| Table 1 | |
| Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
| Drug-Related Increases | |
| <18 | 14 additional cases |
| 18-24 | 5 additional cases |
| Drug-Related Decreases | |
| 25-64 | 1 fewer case |
| >65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION - Discontinuation of Treatment with Citalopram, for a description of the risks of discontinuation of citalopram).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for citalopram should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder:
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that citalopram is not approved for use in treating bipolar depression.
Potential for Interaction with Monoamine Oxidase Inhibitors
In patients receiving serotonin reuptake inhibitor drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of SSRIs and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that citalopram should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping citalopram before starting an MAOI.
Precautions
General
Discontinuation of Treatment with Citalopram
During marketing of citalopram and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with citalopram. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).
Abnormal Bleeding
Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of citalopram with NSAIDs, aspirin, or other drugs that affect coagulation.
Hyponatremia
Cases of hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in association with citalopram treatment. All patients with these events have recovered with discontinuation of citalopram and/or medical intervention. Hyponatremia and SIADH have also been reported in association with other marketed drugs effective in the treatment of major depressive disorder.
Activation of Mania/Hypomania
In placebo-controlled trials of citalopram, some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1,063 patients treated with citalopram and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants. As with all antidepressants, citalopram should be used cautiously in patients with a history of mania.
Seizures
Although anticonvulsant effects of citalopram have been observed in animal studies, citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of citalopram, seizures occurred in 0.3% of patients treated with citalopram (a rate of one patient per 98 years of exposure) and 0.5% of patients treated with placebo (a rate of one patient per 50 years of exposure). Like other antidepressants, citalopram should be introduced with care in patients with a history of seizure disorder.
Interference with Cognitive and Motor Performance
In studies in normal volunteers, citalopram in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect their ability to engage in such activities.
Use in Patients with Concomitant Illness
Clinical experience with citalopram in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using citalopram in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.
Citalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing. However, the electrocardiograms of 1,116 patients who received citalopram in clinical trials were evaluated and the data indicate that citalopram is not associated with the development of clinically significant ECG abnormalities.
In subjects with hepatic impairment, citalopram clearance was decreased and plasma concentrations were increased. The use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION).
Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with citalopram, however, it should be used with caution in such patients (see DOSAGE AND ADMINISTRATION).
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe citalopram.
Although in controlled studies citalopram has not been shown to impair psychomotor performance, any psychoactive drug may impair judgment, thinking or motor skills, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect their ability to engage in such activities.
Patients should be told that, although citalopram has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of citalopram and alcohol in depressed patients is not advised.
Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.
Patients should be cautioned about the concomitant use of citalopram and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breastfeeding an infant.
While patients may notice improvement with citalopram therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with citalopram and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for citalopram. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking citalopram.
Clinical Worsening and Suicide Risk:
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
CNS Drugs - Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs.
Alcohol - Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram is not recommended.
Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS and WARNINGS.
Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with citalopram.
Cimetidine - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown.
Digoxin - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.
Lithium - Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram and lithium are coadministered.
Pimozide - In a controlled study, a single dose of pimozide 2 mg coadministered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.
Theophylline - Combined administration of citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.
Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised.
Warfarin - Administration of 40 mg/day citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.
Carbamazepine - Combined administration of citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered.
Triazolam - Combined administration of citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.
Ketoconazole - Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
CYP3A4 and 2C19 Inhibitors - In vitro studies indicated that CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram. However, coadministration of citalopram (40 mg) and ketoconazole (200 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance.
Metoprolol - Administration of 40 mg/day citalopram for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram and metoprolol had no clinically significant effects on blood pressure or heart rate.
Imipramine and Other Tricyclic Antidepressants (TCAs) - In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with citalopram.
Electroconvulsive Therapy (ECT) -There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m2) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD, respectively, on a mg/m2 basis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.
Mutagenesis
Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.
Impairment of Fertility
When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses ≥ 32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body surface area (mg/m2) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD.
Pregnancy
Pregnancy Category C
In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.
In two rat embryo/fetal development studies, oral administration of citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a body surface area (mg/m2) basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/m2 basis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/m2 basis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit.
When female rats were treated with citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD on a mg/m2 basis. The no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m2 basis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m2 basis. A no-effect dose was not determined in that study.
There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy - Nonteratogenic Effects
Neonates exposed to citalopram and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS).
When treating a pregnant woman with citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).
Labor and Delivery
The effect of citalopram on labor and delivery in humans is unknown.
Nursing Mothers
As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother, and in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or citalopram therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram treatment for the mother.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS - Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with citalopram, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of citalopram in a child or adolescent must balance the potential risks with the clinical need.
Geriatric Use
Of 4,422 patients in clinical studies of citalopram, 1,357 were 60 and over, 1,034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Most elderly patients treated with citalopram in clinical trials received daily doses between 20 and 40 mg (see DOSAGE AND ADMINISTRATION).
In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively (see CLINICAL PHARMACOLOGY).
20 mg/day is the recommended dose for most elderly patients (see DOSAGE AND ADMINISTRATION).
Adverse Reactions
The premarketing development program for citalopram included citalopram exposures in patients and/or normal subjects from 3 different groups of studies: 429 normal subjects in clinical pharmacology/pharmacokinetic studies; 4,422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to a
Subscribe to:
Comments (Atom)