EFEXOR® XR
VENLAFAXINE HYDROCHLORIDE MODIFIED RELEASE CAPSULES
Description
EFEXOR-XR capsules are an extended-release formulation which release the active constituent, venlafaxine hydrochloride, from spheroids within the capsule. There are two strengths of EFEXOR-XR capsules, which contain 75 mg or 150 mg of venlafaxine. Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH dependent. It is chemically defined (R/S)-1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride. Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride).
Other constituents are cellulose, ethylcellulose, hypromellose, gelatin, red and yellow iron oxides and titanium dioxide.
PHARMACOLOGY
Actions
Venlafaxine is a structurally novel antidepressant for oral administration; it is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents.
The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of serotonin and noradrenaline reuptake, and also weakly inhibit dopamine reuptake. Venlafaxine is a racemate. The R-enantiomer is relatively more potent than the S-enantiomer with regard to inhibition of noradrenaline reuptake; the S-enantiomer is more potent regarding inhibition of serotonin reuptake. Both enantiomers are more potent on serotonin compared to noradrenaline reuptake. The enantiomers of ODV also inhibit both noradrenaline and serotonin reuptake, with the R-enantiomer being more potent. Venlafaxine and its major metabolite appear to be equipotent with respect to their overall action on neuro transmitter re-uptake and receptor binding. Studies in animals show that tricyclic antidepressants may reduce β-adrenergic receptor responsiveness following chronic administration. In contrast, venlafaxine and ODV reduce β-adrenergic responsiveness after both acute (single dose) and chronic administration.
Venlafaxine has virtually no affinity for rat brain muscarinic, H1-histaminergic or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors may be related to various side effects seen with other antidepressant medications, such as sedative, cardiovascular, and anticholinergic effects. Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.
In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine also does not produce noradrenaline release from brain slices. It has no significant central nervous system (CNS) stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.
Clinical studies have been conducted to examine the effects of venlafaxine on behavioural performance of healthy individuals. Results from these studies indicate no clinically significant impairment of psychomotor, cognitive, or complex behaviour performance.
There have been no clinical studies to evaluate the benefit of combined use of EFEXOR-XR with electroconvulsive therapy and other antidepressants (eg lithium, anticonvulsants, thyroid hormones).
Pharmacokinetics
Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively.
Absorption
On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed, indicating that absorption of venlafaxine is nearly complete. However, the presystemic metabolism of venlafaxine (which primarily forms the active metabolite, ODV) reduces the absolute bioavailability of venlafaxine to 42%±15%.
After administration of EFEXOR-XR, the peak plasma concentrations of venlafaxine and ODV are attained within 6.0±1.5 and 8.8±2.2 hours, respectively. The rate of absorption of venlafaxine from the EFEXOR-XR capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of EFEXOR-XR (15±6 hours) is actually the absorption half-life instead of the true disposition half-life (5±2 hours) observed following administration of an immediate-release tablet.
When equal doses of venlafaxine, administered either as an immediate-release tablet taken in divided doses or as a modified release capsule, taken once a day, the exposure (AUC, area under the concentration curve) to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower following treatment with the EFEXOR-XR capsule. Therefore, the EFEXOR-XR capsule provides a slower rate of absorption, but the same extent of absorption (i.e., AUC), as the venlafaxine immediate-release tablet.
Distribution
The degree of binding of venlafaxine to human plasma proteins is 27%±2% at concentrations ranging from 2.5 to 2215 ng/mL, and the degree of ODV binding to human plasma proteins is 30%±12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with concomitantly administered venlafaxine are not expected. Following intravenous administration, the steady-state volume of distribution of venlafaxine is 4.4±1.9 L/kg, indicating that venlafaxine distributes well beyond the total body water.
Metabolism
Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. The primary metabolite of venlafaxine is ODV, but venlafaxine is also metabolised to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalysed by CYP2D6 and that the formation of N-desmethylvenlafaxine is catalysed by CYP3A3/4. The results of the in vitro studies have been confirmed in a clinical study with subjects who are CYP2D6 poor and extensive metabolisers. However, despite the metabolic differences between the CYP2D6 poor and extensive metabolisers, the total exposure to the sum of the two active species (venlafaxine and ODV) was similar in the two metaboliser groups. Therefore, CYP2D6 poor and extensive metabolisers can be treated with the same regimen of EFEXOR-XR.
Excretion
Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours after a single radio-labelled dose as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%), and 92% of the radioactive dose is recovered within 72 hours. Therefore, renal elimination of venlafaxine and its metabolites is the primary route of excretion.
Food-Drug Interactions
Administration of EFEXOR-XR with food has no effect on the absorption of venlafaxine or on the subsequent formation of ODV.
Subject age and sex do not significantly affect the pharmacokinetics of venlafaxine. A 20% reduction in clearance was noted for ODV in subjects over 60 years old; this was probably caused by the decrease in renal function that typically occurs with aging. No accumulation of venlafaxine or ODV has been observed during chronic administration in healthy subjects.
In some patients with compensated hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered. The reduction in both the metabolism of venlafaxine and elimination of ODV resulted in higher plasma concentrations of both venlafaxine and ODV.
In patients with moderate to severe impairment of renal function, the total clearance of both venlafaxine and ODV was reduced, and t½ was prolonged. The reduction in total clearance was most pronounced in subjects with creatinine clearance less than 30 mL/min.
Clinical Trials
Use in Depression
Three double blind, placebo controlled trials, of up to 12 weeks duration, have examined the clinical efficacy of EFEXOR-XR in the treatment of major depression. One of these studies also incorporated an active comparator, paroxetine. These studies showed EFEXOR-XR to have greater efficacy than both placebo and paroxetine in reducing depression.
Use in Anxiety
The efficacy of EFEXOR-XR capsules as a treatment for anxiety was demonstrated in four placebo-controlled trials. Two were eight-week studies, utilizing EFEXOR-XR doses of 75 mg, 150 mg and 225 mg/day and of 75 mg and 150 mg/day, and the others were the first eight-weeks of two long term studies, utilizing EFEXOR-XR doses of 75 mg-225 mg/day and of 37.5 mg, 75 mg and 150 mg/day. Each of the four studies demonstrated superiority of EFEXOR-XR over placebo on at least five of the following efficacy scales: HAM_A total score, the HAM-A psychic anxiety factor, the Hospital Anxiety and Depression (HAD) anxiety subscale, and the CGI severity of illness scale, as well as the HAM-A anxious mood and tension item.
Two of the four studies continued for up to six months. These two studies, which utilized EFEXOR-XR doses of 75 mg-225 mg/day and 37.5 mg, 75 mg and 150 mg/day demonstrated superiority of EFEXOR-XR over placebo on the HAM-A total score, HAM-A psychic anxiety factor, the HAD anxiety factor, and the CGI severity of illness scale, as well as the HAM-A anxious mood item.
Indications
EFEXOR-XR is indicated for the treatment of major depression including depression with associated anxiety.
EFEXOR-XR is also indicated for the treatment of Generalized Anxiety Disorder, including long term treatment.
Contra-Indications
EFEXOR-XR is contraindicated in patients known to be hypersensitive to it.
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated - See PRECAUTIONS - Interactions with other drugs.
Precautions
Use with caution in the following circumstances
Renal or Hepatic Impairment: In patients with moderate to severe renal impairment or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary in these patients. EFEXOR-XR should be used with caution in such patients.
Other Concomitant Conditions: Cases of hyponatraemia, secondary to a transient syndrome of inappropriate antidiuretic hormone secretion (SIADH) have rarely been reported with antidepressants including SSRIs, usually in the elderly and in patients taking diuretics or who are otherwise volume depleted. Rare cases of hyponatraemia have been reported with venlafaxine, usually in the elderly. These have resolved on discontinuation of the drug.
No clinical experience with venlafaxine in patients with concomitant medical illness is available yet. Caution is advised in administering EFEXOR-XR to patients with diseases or conditions that could affect haemodynamic responses or metabolism.
Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from any clinical studies during the product's trials. The mean heart rate was increased by approximately 4 beats/minute during treatment. Clinically significant electrocardiogram findings were observed in 0.9% of venlafaxine-treated patients and 0.3% of placebo-treated patients. Clinically significant changes in PR, QRS or QTc intervals were rarely observed in patients treated with venlafaxine during pre-marketing trials.
Other Considerations
Abrupt Discontinuation of EFEXOR-XR: Discontinuation symptoms have been assessed both in patients with depression and in those with anxiety. Abrupt discontinuation, dose reduction, or tapering of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Symptoms reported included agitation, anxiety, confusion, dry mouth, fatigue, paresthesias, vertigo, hypomania, nausea, vomiting, dizziness, headache, diarrhoea, sleep disturbance, insomnia, sweating and nervousness. Where such symptoms occurred, they were usually self-limiting, but in a few patients lasted for several weeks. Discontinuation effects are well known to occur with antidepressants. There is also a report of a withdrawal syndrome, confirmed by two challenges in a 32 year old woman who had received venlafaxine 300 mg daily for 8 months. It is therefore recommended that the dosage of EFEXOR-XR be tapered gradually and the patient monitored. The period required for discontinuation may depend on the dose, duration of therapy and the individual patient (See DOSAGE AND ADMINISTRATION).
Altered Weight. Weight changes, either losses or gains, do not appear to present a clinically important feature of venlafaxine treatment. Clinically significant weight gain or loss was seen in less than 1% of patients treated with venlafaxine during clinical trials. A dose-dependent weight loss (mean loss, <1 kg) was noted in some patients treated with venlafaxine during the first few months of venlafaxine treatment. After month 9, the mean weight began to increase slightly but significantly, an effect often seen with tricyclic antidepressant therapy. Significant weight loss (≥ 7 kg) was seen in 6 (0.3%) of 2,181 patients, compared to no patients treated with placebo and 0.2% of patients treated with a comparative antidepressant.
Suicide. The risk of suicide must be considered in all depressed patients. Prescriptions for EFEXOR-XR should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the possibility of overdosage.
Seizures. In all pre-marketing depression trials with venlafaxine, seizures were reported in 0.3% of all venlafaxine-treated patients. All patients recovered. No seizures occurred in EFEXOR-XR-treated patients. EFEXOR-XR, as with all antidepressants, should be introduced with care, in patients with a history of seizure disorders. EFEXOR-XR should be discontinued in any patient who develops seizures.
Mania/Hypomania. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder treated with other antidepressants. During all clinical trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. There were no reports of mania or hypomania in anxiety studies with EFEXOR-XR.
Skin/Allergic reactions. Patients should be advised to notify their physician if they develop a rash, hives, or related allergic phenomena.
Effects on cognitive and motor performance. Although venlafaxine has been shown not to affect psychomotor, cognitive or complex behaviour performance in healthy volunteers, any psychoactive medication may impair judgment, thinking or motor skills, and patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the treatment does not affect them adversely.
Check the following before use
Physical and Psychological Dependence. (see Pharmacology). Clinical studies have shown no evidence of drug-seeking behaviour, development of tolerance, or dose escalation over time among patients taking venlafaxine. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely observing them for signs of misuse or abuse of venlafaxine (e.g. development of tolerance, increase in dose, drug-seeking behaviour).
Use in Elderly Patients
No overall differences in effectiveness or safety were observed between elderly (aged 65 years and older) and younger patients. EFEXOR-XR does not appear to pose any exceptional safety problems for healthy elderly patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Evidence of impairment of fertility was not noted in nonclinical toxicology studies.
Venlafaxine was given by oral gavage to mice and rats for 18 months and 24 months respectively, at dosages up to 120 mg/kg/day. There were no clear drug-related oncogenic effects in either species. In these studies, animal exposure to the main human metabolite ODV was less, and exposure to venlafaxine was more than would be expected in humans taking the recommended therapeutic and maximum doses.
There was no evidence of gene mutation or chromosomal change in a series of genotoxicity assays using venlafaxine and the main human metabolite ODV.
Signs of pharmacologic toxicity were seen in paternal and maternal rats given venlafaxine doses of 30 and 60 mg/kg/day, but no adverse effect was noted in fertility or general reproductive performance. Decreased foetal size and pup weight at birth with 60 mg/kg/day may be correlated with maternal toxicity.
Use During Pregnancy
Category: B2
In a rat teratology study, venlafaxine was given orally at dosages up to 80 mg/kg/day (approximately 11 times the maximum recommended human dose). Foetotoxicity evidenced by growth retardation, was slightly increased at 80 mg/kg/day, an effect which may be related to maternal toxicity at this dose level. Foetal survival and morphologic development were not affected. In another teratology study, rabbits were given venlafaxine dosages up to 90 mg/kg/day. Foetotoxicity evidenced by resorption and foetal loss were slightly increased at 90 mg/kg/day; (approximately 12 times the maximum recommended human dose). These effects could be correlated with maternal toxicity. No venlafaxine-associated teratogenic effect was noted in either species at any dosage, though there was an increased incidence of 'W'-shaped apex of the heart in the rabbit study. In these studies, animal exposure to the main human metabolite ODV was less, and estimated exposure to venlafaxine was approximately 6-fold more, than would be expected in humans taking the recommended therapeutic and maximum doses. In rats, estimated exposure to venlafaxine was more than the expected human exposure. No teratogenic effect was seen.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this medication should be used during pregnancy only if clearly needed. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
In a perinatal toxicity study in rats after oral dosing of dams with 30 mg/kg or more, decreased pup survival following birth was observed. This effect is secondary to treatment-decreased maternal care, and is also seen with other antidepressants.
Use During Lactation
Venlafaxine and/or its metabolites are secreted in milk of lactating rats at concentrations higher than those found in the plasma of the dam. Venlafaxine and its metabolites have been shown to pass into human milk. Therefore, the use of EFEXOR-XR in nursing women cannot be recommended.
Paediatric Use
Safety and effectiveness in individuals below 18 years of age have not been established and such use is not recommended.
Interactions with other Drugs
Venlafaxine and ODV are 27% and 30% bound to plasma proteins, therefore interactions due to protein binding of venlafaxine and the major metabolite are not expected.
Monoamine oxidase inhibitors - Concomitant use with EFEXOR-XR is contraindicated. Adverse reactions, some serious, have been reported when venlafaxine therapy is initiated soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of venlafaxine. Reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. Given these reactions, as well as the serious, sometimes fatal interactions reported with concomitant or immediately consecutive administration of MAOIs and other antidepressants with pharmacological properties similar to EFEXOR-XR, do not use EFEXOR-XR in combination with an MAOI or within at least 14 days of discontinuing MAOI treatment. Allow at least 7 days after stopping EFEXOR-XR before starting an MAOI. Hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes including extreme agitation progressing to delirium and coma, and features resembling neuroleptic malignant syndrome have been reported with concomitant selective serotonin reuptake inhibitor/MAOI therapy. Severe hyperthermia and seizures, sometimes fatal, have been reported with concomitant tricyclic antidepressant/MAOI therapy.
There are no clinical trials to support the recommendation of a specific time between discontinuing treatment with the reversible MAOI, moclobemide, and initiating EFEXOR-XR therapy or switching to moclobemide. Given the risk for adverse reactions described for irreversible MAOIs (see PRECAUTIONS), an adequate washout period should be ensured when switching a patient between EFEXOR-XR and moclobemide. The appropriate washout period should take into account the pharmacological properties of venlafaxine and moclobemide and the clinician's assessment of the individual patient. Based on the half lives of moclobemide, venlafaxine and ODV, the minimum washout period should be 24 hours when switching from moclobemide to EFEXOR-XR and 7 days when switching from EFEXOR-XR to moclobemide.
EFEXOR-XR should not be administered concomitantly with moclobemide (see PRECAUTIONS).
The risk of using EFEXOR-XR in combination with other CNS-active medications has not been systemically evaluated (except in the cases listed below). Consequently caution is advised if the concomitant administration of EFEXOR-XR and such medication is required.
No information is available on the use of EFEXOR-XR in combination with opiates.
Venlafaxine did not affect the CYP2D6-mediated 2-hydroxylation of imipramine or its active metabolite, desimipramine, which indicates that venlafaxine does not inhibit the CYP2D6 isozyme. However, the renal clearance of 2-hydroxydesimipramine was reduced with coadministration of venlafaxine.
Cimetidine inhibited the first-pass metabolism of venlafaxine but had no apparent effect on the formation or elimination of ODV, which is present in much greater quantity in the systemic circulation. No dosage adjustment seems necessary when EFEXOR-XR is coadministered with cimetidine. However, for elderly patients or patients with hepatic dysfunction, the interaction could potentially be more pronounced and for such patients clinical monitoring is indicated when EFEXOR-XR is administered with cimetidine.
The pharmacokinetic profiles of venlafaxine and ODV were not altered when venlafaxine and diazepam, or venlafaxine and lithium, were administered together to healthy volunteers. Venlafaxine had no effect on the pharmacokinetic profiles of diazepam or lithium in these studies. Administration of venlafaxine did not affect the psychomotor and psychometric effects induced by diazepam.
Retrospective analysis of study events occurring in patients taking venlafaxine concurrently with antihypertensive or hypoglycaemic agents in clinical trials provided no evidence suggesting incompatibility between treatment with venlafaxine and treatment with either antihypertensive or hypoglycaemic agents.
The pharmacokinetic profiles of venlafaxine, ODV and ethanol (alcohol) were not altered when venlafaxine and ethanol were administered together to healthy volunteers on an occasional basis. The administration of venlafaxine in a stable regimen did not potentiate the psychomotor and psychometric effects induced by ethanol in patients.
Venlafaxine administered under steady-state conditions (75 mg twice daily) to 24 healthy subjects decreased total oral clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t½) was unchanged. The mechanism explaining this finding is unknown.
There have been no clinical studies to evaluate the benefit of the combined use of EFEXOR-XR with electroconvulsive therapy or other antidepressants (e.g. lithium, anticonvulsants, thyroid hormones). The benefit of combining electroconvulsive therapy with EFEXOR-XR therapy has not been evaluated.
There have been reports of elevated clozapine levels in association with adverse events including seizures, following the administration of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy
Drugs that Inhibit Cytochrome P450 Isoenzymes
CYP2D6 Inhibitors - In vitro and in vivo studies indicate that venlafaxine is metabolised predominantly to ODV by CYP2D6, the isozyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism (such as amiodarone and quinidine) and venlafaxine. Drug interactions that reduce the metabolism of venlafaxine to ODV potentially increase the plasma concentrations of venlafaxine and lower the concentration of the active metabolite. However, because the two primary metabolic pathways for venlafaxine are through CYP2D6 and, to a lesser extent, CYP3A4, concomitant intake of CYP2D6 inhibitors is not recommended during treatment with venlafaxine. Specific studies on the interactions between venlafaxine and both these inhibitors, however, have not been performed.
Imipramine partially inhibited the CYP2D6-mediated formation of ODV, however, the total concentrations of active compounds (venlafaxine plus ODV) was not affected with imipramine administration. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolisers, the total sum of the two active species (venlafaxine and ODV) was similar in the two metaboliser groups. Therefore, no dosage adjustment is expected when venlafaxine is coadministered with a CYP2D6 inhibitor.
CYP3A4 Inhibitors - In vitro studies indicate that venlafaxine is likely metabolised to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between inhibitors of CYP3A4-mediated metabolism (such as erythromycin, fluconazole and grapefruit juice) and venlafaxine is small. However, concomitant intake of CYP3A4 inhibitors during treatment with venlafaxine is not recommended.
Drugs Metabolised by Cytochrome P450 Isoenzymes
In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6, and that venlafaxine does not inhibit CYP1A2, CYP2C9 or CYP3A4. Some of these findings have been confirmed with drug interaction studies between venlafaxine and imipramine (metabolised by CYP2D6) and diazepam (metabolised by CYP2C19). Therefore, EFEXOR-XR is not expected to interact with other drugs metabolised by these isozymes.
Adverse Reactions
The most commonly observed adverse events associated with the use of immediate-release venlafaxine or EFEXOR-XR and not seen at an equivalent incidence among placebo-treated patients were nervous system complaints, including blurred vision, dizziness, dry mouth, insomnia, nervousness, tremor and somnolence; gastrointestinal complaints including anorexia, constipation, vomiting and nausea; and abnormal ejaculation/orgasm, impotence, anxiety, sweating, and asthenia.
The occurrence of many of these observed adverse effects was dose related. Adverse events generally decrease in intensity and frequency with continued therapy.
A two- to three-fold reduction in the incidence and severity (visual analogue scale) of nausea was observed with EFEXOR-XR compared with immediate-release venlafaxine in clinical pharmacology studies with non-depressed subjects. In clinical studies, the incidence of nausea and the adaptation to nausea appeared to be improved with EFEXOR-XR compared with immediate-release venlafaxine.
The following adverse events were reported in a total of 5079 patients exposed to venlafaxine during all pre-marketing trials. All reported events are included except those for which a drug cause was remote. Although the events reported did occur during treatment with venlafaxine, they were not necessarily caused by treatment. Adverse events reported with immediate-release venlafaxine, but not with EFEXOR-XR, have been excluded from the listings below.
Events are further classified within body system: Frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in fewer than 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body as a whole:
Frequent (more than 3%): Abdominal pain, accidental injury, asthenia, back pain, flu syndrome, headache, infection, pain.
(more than 1%): chest pain, neck pain, chills, fever, chest pain.
Infrequent (less than 1%): allergic reaction substernal, cyst, generalised oedema, hernia, malaise, moniliasis, neck rigidity, photosensitivity reaction, face oedema, pelvic pain, suicide attempt
Rare (less than 0.1%): withdrawal syndrome, body odour, cellulitis, halotosis.
Cardiovascular system:
Frequent (more than 3%): hypertension, vasodilation.
(more than 1%): migraine, palpitation, postural hypotension, tachycardia.
Infrequent (less than 1%): angina pectoris, arrhythmia, extrasystole, hypotension, syncope.
Rare (less than 0.1%): bundle branch block, congestive heart failure, coronary artery disease, mitral valve disorder, myocardial infarct, vascular disorder, bigeminy, pallor, mucocutaneous haemorrhage, venous insufficiency.
Digestive system:
Frequent (more than 3%): anorexia, constipation, diarrhoea, dyspepsia , nausea, vomiting.
(more than 1%): eructation, flatulence, increased appetite.
Infrequent (less than 1%): bruxism, colitis, dysphagia, oesophagitis, gastritis, gastroenteritis, gingivitis, glossitis, rectal haemorrhage, haemorrhoids, oral moniliasis, stomatitis, gastrointestinal ulcer, mouth ulceration.
Rare (less than 0.1%): haematemesis, gum haemorrhage, increased salivation, tongue discolouration.
Haemic and lymphatic system:
Frequent (more than 1%): ecchymosis.
Infrequent (less than 1%): anaemia, thrombocythaemia, leukocytosis, leukopenia, lymphadenopathy.
Metabolic and nutritional:
Frequent (more than 1%): weight gain, weight loss, oedema.
Infrequent (less than 1%): hyperlipaemia, hypokalaemia, peripheral oedema, SGOT increased, thirst, hyperglycaemia, gout.
Rare (less than 0.1%): bilirubinaemia, dehydration, diabetes mellitus, hypoglycaemia, hypoproteinaemia
Musculoskeletal system:
Frequent (more than 1%): arthralgia, myalgia.
Infrequent (less than 1%): arthritis, bone pain, bursitis, leg cramps, myasthenia, tenosynovitis.
Rare (less than 0.1%): rheumatoid arthritis
Nervous system:
Frequent (more than 3%): abnormal dreams, agitation, anxiety, depression, dizziness, dry mouth, hypertonia, insomnia, nervousness, paraesthesia, somnolence, tremor.
(more than 1%): amnesia, confusion, depersonalisation, emotional lability, hypaesthesia, libido decreased, sleep disturbance, thinking abnormal, urinary retention, urinary frequency, vertigo.
Infrequent (less than 1%): apathy, ataxia, CNS stimulation, euphoria, hostility, hyperaesthesia, circumoral paraesthesia, hyperkinesia, hypotonia, incoordination, manic reaction, myoclonus, neuralgia, neuropathy, psychotic depression, paranoid reaction, abnormal speech, stupor, trismus, twitching.
Rare (less than 0.1%): akathisia, aphasia, loss of consciousness, facial paralysis, abnormal gait, hypokinesia, nystagmus, reflexes decreased, reflexes increased, suicidal ideation.
Respiratory system.
Frequent (more than 3%): pharyngitis, rhinitis, sinusitis.
(more than 1%): bronchitis, cough increased, dyspnoea, yawn
Infrequent (less than 1%): asthma, chest congestion, epistaxis, hyperventilation, laryngitis, laryngismus, pneumonia, voice alteration.
Rare (less than 0.1%): hiccup, hypoventilation, hypoxia, pleurisy, sleep apnoea, sputum increased.
Skin and appendages:
Frequent (more than 3%): rash, sweating.
(more than 1%): pruritus
Infrequent (less than 1%): acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema, fungal dermatitis, herpes simplex, skin hypertrophy, maculopapular rash, psoriasis, urticaria.
Rare (less than 0.1%): erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, skin discolouration, vesiculobullous rash, pustular rash, skin striae.
Special senses:
Frequent (more than 3%): abnormality of accommodation.
(more than 1%): abnormal vision, ear pain, mydriasis, taste perversion, tinnitus.
Infrequent (less than 1%): conjunctivitis, corneal lesion, eye pain, diplopia, dry eyes, hyperacusis, otitis media, parosmia, taste loss, visual field defect.
Rare (less than 0.1%): blepharitis, deafness, exophthalmos, glaucoma, labyrinthitis, miosis, otitis externa, subconjunctival haemmorhage, vitreous disorder.
Urogenital system:
Frequent (more than 3%): abnormal ejaculation-male*, dysmenorrhoea*, impotence*.
(more than 1%): anorgasmia-male*, anorgasmia-female*, menstrual disorder*, metrorrhagia*, urinary tract infection, urination impaired, urinary frequency, vaginitis*, prostatitis*.
Infrequent (less than 1%): albuminuria, amenorrhoea*, cystitis, dysuria, hematuria, female lactation*, leukorrhoea*, menorrhagia*, nocturia, abnormal orgasm-female*, kidney pain, bladder pain, polyuria, pyelonephritis, pyuria, urinary incontinence, urinary urgency, urinary retention, uterine fibroids enlarged*, vaginal haemorrhage*, vaginal moniliasis*, breast pain.
Rare (less than 0.1%): oligouria, orchitis, kidney calculus, ovarian cyst*, uterine spasm*, fibrocysytic breast, gynecomastia*.
*Based on the number of men and women as appropriate.
Treatment with venlafaxine has been associated with an increase in blood pressure in some patients. During pre-marketing trials, mean increases in supine diastolic blood pressure of approximately 1 mm Hg were observed in venlafaxine-treated patients compared with decreases of approximately 1 mm Hg in placebo-treated patients. Of the patients who received venlafaxine, 1.8% were judged to have clinically significant blood pressure increases compared with 0.3% of placebo-treated patients. In studies with venlafaxine, the increases in blood pressure were dose related. In general, patients treated with <200 mg per day, showed minor increases, while in a short-term dose ranging study, the highest dose (300-375 mg/day) was associated with mean increases in supine diastolic blood pressure of approximately 4 mm Hg by week 4, and 7 mm Hg by week 6. The presence of treated hypertension or elevated blood pressure at baseline did not seem to predispose patients to further increases during venlafaxine therapy. For patients treated with doses greater than 200 mg/day routine blood pressure monitoring may be advisable.
EFEXOR-XR has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Clinically significant electrocardiogram findings were observed in 0.9% of venlafaxine-treated patients in all pre-marketing trials, compared with 0.3% of placebo-treated patients. Clinically significant changes in PR, QRS, or QTc intervals were rarely observed in patients treated with venlafaxine. The mean heart rate was increased by approximately 4 beats/minute during treatment with venlafaxine.
Dosage and Administration
Usual Dose
The usual recommended dose for the treatment of depression or generalized anxiety disorder is 75 mg per day given once daily. If after two weeks further clinical improvement is required, the dose may be increased to 150 mg per day given once daily. If needed, this can be increased up to 225 mg given once daily. Dose increments should be made at intervals of approximately 2 weeks or more, but not less than 4 days.
The recommended dose is based on results of clinical trials in which EFEXOR-XR was mostly given once daily in doses from 75 to 225 mg. Antidepressant activity with the 75 mg dose was observed after 2 weeks of treatment and anxiolytic activity was observed after one week.
It is recommended that EFEXOR-XR be taken with food. Each capsule should be swallowed whole with fluid. Do not divide, crush, chew or place the capsule in water. EFEXOR-XR should be administered once daily, at approximately the same time either in the morning or in the evening.
Depressed patients who are currently being treated at a therapeutic dose with immediate-release venlafaxine may be switched to EFEXOR-XR at the nearest equivalent dose (mg/day). However, individual dosage adjustments may be necessary.
Patients with Renal or Hepatic Impairment
Patients with renal and/or hepatic impairment should receive lower doses of EFEXOR-XR. It may be necessary to initiate treatment in these patients with immediate-release venlafaxine tablets. Patients whose glomerular filtration rate (GFR) is less than 30 mL/min should have their dosage reduced by 50%. Haemodialysis clearances of both venlafaxine and ODV in humans are low. Nonetheless, it is recommended that the daily dose of EFEXOR-XR be withheld from patients who require dialysis treatment until after completion of the dialysis treatment. Patients with moderate hepatic impairment, should also have their dosage reduced by 50%. Further reductions in dosage should be considered for patients with more severe degrees of hepatic impairment.
Elderly Patients
No adjustment in the usual dose is recommended for elderly patients solely because of their age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualising the dosage, extra care should be taken when increasing the dose.
Maintenance/Continuation/Extended Treatment
The physician should periodically re-evaluate the usefulness of long-term EFEXOR-XR treatment for the individual patient. It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.
Discontinuing EFEXOR-XR
When EFEXOR-XR at a dose of 75 mg/day or greater has been administered for more than 1 week is stopped, it is generally recommended that the dose be tapered gradually to minimise the risk of discontinuation symptoms. Patients who have received EFEXOR-XR for 6 weeks or more should have their dose tapered gradually over a 1-week period. Patients should be advised to consult their physician before abruptly discontinuing EFEXOR-XR.
Overdosage
In managing overdosage, consider the possibility of multiple medication involvement. The physician should consider contacting a poison control centre on the treatment of any overdose. (See PRECAUTIONS - Interactions with other drugs)
During pre-marketing trials, most patients who have overdosed with venlafaxine were asymptomatic. Of the remainder, somnolence was the most commonly reported symptom. Mild sinus tachycardia has also been reported. There were no reports of seizures, respiratory distress, significant cardiac disturbances, or significant laboratory test results abnormalities among any of the cases reported to date. However, seizures and respiratory distress occurred in one additional patient in an on-going study who ingested an estimated 2.75 g of venlafaxine with naproxen and thyroxine. Generalised convulsions and coma resulted and emergency resuscitation was required. Recovery was good without sequelae.
In post-marketing experience, electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, change in level of consciousness (ranging from somnolence to coma), and seizures have been reported in association with overdosage of venlafaxine, either alone or in combination with other drugs and/or alcohol. Such events are rare and usually resolved spontaneously. Also from post-marketing experience, there have been reports of fatalities in patients taking overdoses of venlafaxine, predominantly in combination with alcohol and/or other drugs.
Management of Overdosage - Ensure an adequate airway, oxygenation and ventilation. Monitoring of cardiac rhythm and vital signs is recommended. General supportive and symptomatic measures are also recommended. Use of activated charcoal, induction of emesis or gastric lavage should be considered. No specific antidotes for venlafaxine are known. Venlafaxine and ODV are not considered dialyzable because haemodialysis clearance of both compounds are low.
Presentation
EFEXOR-XR is available for oral use as opaque peach (75 mg) or opaque dark orange (150 mg) modified release capsules with a 'W' and strength printed in red or white, respectively.
EFEXOR-XR is packed in blister packs and high density polyethylene (HDPE) bottles in pack sizes of 28.
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