d367c venlor xr 37.5,75, 150 cap. enclo - cipla … · d367c venlor xr 37.5,75, 150 cap. enclo.pmd...
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SCHEDULING STATUS: S5
PROPRIETARY NAME (AND DOSAGE FORM):
VENLOR XR 37.5 (Capsules).VENLOR XR 75 (Capsules).VENLOR XR 150 (Capsules).
COMPOSITION:VENLOR XR 37.5 CAPSULES: Each extended release capsule contains venlafaxine hydrochloride equivalentto 37.5 mg venlafaxine.VENLOR XR 75 CAPSULES: Each extended release capsule contains venlafaxine hydrochloride equivalentto 75 mg venlafaxine.VENLOR XR 150 CAPSULES: Each extended release capsule contains venlafaxine hydrochloride equivalentto 150 mg venlafaxine.
PHARMACOLOGICAL CLASSIFICATION:A 1.2 Psychoanaleptics (antidepressants).
PHARMACOLOGICAL ACTION:Pharmacodynamics:Venlafaxine and its major metabolite, O-desmethylvenlafaxine, are both serotonin and noradrenalinere-uptake inhibitors. Both also weakly inhibit the re-uptake of dopamine. This effectively potentiatesneurotransmitter activity in the central nervous system (CNS). Following both acute (single dose) andchronic administration, venlafaxine and O-desmethylvenlafaxine reduce responsiveness tobeta-adrenergic stimulation. With respect to their overall action on receptor binding and the re-uptake ofneurotransmitters, venlafaxine and O-desmethylvenlafaxine appear to be equipotent.
Pharmacokinetics:Venlafaxine is well absorbed from the gut. After absorption it is extensively metabolised by first-passmechanisms. Following VENLOR XR administration, peak plasma concentrations of venlafaxine and O-desmethylvenlafaxine are reached after 6.5 1.5, and 10.5 1.4 hours, respectively. Extensive hepaticmetabolism of venlafaxine results in the release of the major active metabolite, O-desmethylvenlafaxine.Venlafaxine and O-desmethylvenlafaxine have mean disposition half-lives of approximately 5 and 11 hours,respectively. The doses and plasma concentrations of venlafaxine and O-desmethylvenlafaxine generallycorrelate well. Less than 35% of venlafaxine and O-desmethylvenlafaxine are bound to plasma proteins (27%venlafaxine and 30% O-desmethylvenlafaxine are plasma protein bound, respectively).The kidneys are the major route of excretion for both venlafaxine and its metabolites. Within 48 hours ofadministration, approximately 87 % of a venlafaxine dose is recovered in the urine as unchanged venlafaxine,unconjugated O-desmethylvenlafaxine, conjugated O-desmethylvenlafaxine, or other minor metabolites.The extent of absorption of VENLOR XR is not altered by food. Food also does not affect the formation of O-desmethylvenlafaxine.
Elderly: In subjects over 60 years of age, a 20 % reduction in clearance of O-desmethylvenlafaxine is noted.
Renal impairment: The total clearance of both venlafaxine and O-desmethylvenlafaxine is reduced, and tprolonged, in patients with moderate to severe renal impairment. This reduction in total clearance is mostprominent in patients with creatinine clearance < 30 ml/min. Dosages should be adjusted in this patient group(see DOSAGE AND DIRECTIONS FOR USE).Hepatic impairment: The phamacokinetic disposition of both venlafaxine and O-desmethylvenlafaxine issignificantly altered in patients with compensated hepatic cirrhosis. As both the metabolism of venlafaxine andthe elimination of O-desmethylvenlafaxine are reduced, higher plasma concentrations of both molecules areencountered. Dosages should be adjusted in this patient group (see DOSAGE AND DIRECTIONS FORUSE).INDICATIONS:VENLOR XR is indicated for the following:
The treatment of depression, including depression with associated anxiety. Prevention of relapse of an episode of depression in patients that responded to an initial 6 to 8 weeks
period of treatment. Prevention of recurrence in patients responding to 6 months of relapse prevention. Clinical studies
have not demonstrated the safety and efficacy of treatment beyond one year. The treatment of generalised anxiety disorder. Treatment of social anxiety disorder. The effectiveness of VENLOR XR has not been demonstrated
for longer than 12 weeks for this indication.
CONTRA-INDICATIONS:Hypersensitivity to VENLOR XR or any of its ingredients.Children younger than 18 years.Pregnancy and lactation (see PREGNANCY AND LACTATION).Administration to patients using monoamine oxidase inhibitors (MAOIs) concomitantly (see WARNINGS).WARNINGS:Initiation of VENLOR XR therapy soon after discontinuation of a MAOI and initiation of MAOI therapy soonafter discontinuation of VENLOR XR have resulted in severe adverse reactions. These reactions haveincluded nausea, vomiting, tremor, myoclonus, dizziness, diaphoresis, flushing and hyperthermia with featuresapparently similar to neuroleptic malignant syndrome, seizures and death. VENLOR XR therapy should notcommence within 2 weeks of discontinuing MAOI therapy. At least 1 week should be allowed between startingMAOI therapy and discontinuing treatment with VENLOR XR (see INTERACTIONS).Because suicide is a risk in depressed patients, the smallest amount of drug should be prescribed initiallyto reduce the risk of an overdose.The safety and efficacy in children younger than 18 years have not been established (see CONTRA-INDICATIONS and SIDE-EFFECTS AND SPECIAL PRECAUTIONS).Adults as well as children with major depressive disorders may experience worsening of their depression andor the emergence of suicidal ideation and behaviour, irrespective of taking antidepressant medicines. Untilsignificant remission occurs, this remains a risk. No causal role for antidepressant medicine inducing suchbehaviour has been established. Patients on VENLOR XR therapy should nevertheless be closely monitoredfor clinical worsening and suicidality, especially at the beginning of treatment or when doses are increasedor decreased.When treating patients with major depressive disorders, one should take the same precautions as whentreating patients with other psychiatric and non-psychiatric disorders. This is necessary because of thepossible co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders.The symptoms listed below have been reported in patients receiving treatment with antidepressants for eithermajor depressive disorder or for other indications, including both psychiatric and non-psychiatric disorders:agitation, anxiety, panic attacks, irritability, impulsivity, insomnia, hostility (aggressiveness), hypomania, maniaand akathisia. Although a causal link has not been established for the emergence of suicidal impulses, achange in the therapeutic regimen, including possible discontinuation of VENLOR XR, should be consideredin patients with severe suicidal impulses, or when such symptoms are abrupt in onset, or were not part of thepatients presenting symptoms.If it is decided to stop VENLOR XR treatment, the dose should be tapered (see Precautions and DOSAGEAND DIRECTIONS FOR USE).INTERACTIONS:Monoamine oxidase inhibitors: - (see WARNINGS).Recent discontinuation from a MAOI followed by initiation of VENLOR XR, or recent discontinuation fromVENLOR XR, prior to initiation of MAOI may result in emergence of severe adverse reactions (see CONTRA-INDICATIONS).
These reactions include nausea, vomiting, dizziness, tremor, myoclonus, diaphoresis, flushing, hyperthermiawith features resembling neuroleptic malignant syndrome, seizure and death.
CNS active medicines:The mechanism of action of VENLOR XR and its potential for serotonin syndrome should be considered whenVENLOR XR is co-administered with other medicines with serotonergic effects. These include triptans,selective serotonin reuptake inhibitors and lithium. Caution is advised.
Indinavir:When venlafaxine and indinavir are co-administered, a decrease of 28 % in the AUC and a decrease of 36 %in Cmaxfor indinavir are reported. The pharmacokinetics of VENLOR XR and O-desmethylvenlafaxine is notaffected by indinavir. It is unknown what the clinical significance of this interaction is.
Warfarin:VENLOR XR may result in increased anticoagulant effects in patients taking warfarin.Ethanol:Ethanol-inducedimpairment of mental and motor skills may be enhanced by VENLOR XR. The consumptiomof alcohol during VENLOR XR treatment should be discouraged.Haloperidol:Changes in the pharmacokinetics of oral haloperidol include a possible decrease of 42 % in total clearance,a 70 % increase in AUC, and an 88 % increase in the Cmax. The half-life is not affected. This should beconsidered in the co-administration of haloperidol and VENLOR XR.Cimetidine:The first-pass metabolism of VENLOR XR is inhibited by cimetidine. It does not affect the formation orelimination of O-desmethylvenlafaxine, which has a much higher blood concentration. Therefore, the combinedpharmacologic activity of VENLOR XR and O-desmethylvenlafaxine is not expected to increase much.The co-administration of VENLOR XR and cimetidine does not require any dosage adjustments. The extentof the interaction between VENLOR XR and cimetidine in the elderly and in patients with hepatic dysfunctionis not known. Since the interaction can potentially be more pronounced in such patients, clinical monitoringis indicated.
Risperidone:The AUC of risperidone may be increased by 32%, but the pharmacokinetic profile of the total active moiety(risperidone plus 9-hydroxyrisperidone) is not significantly altered by VENLOR XR.Diazepam:The pharmacokinetics of VENLOR XR and O-desmethylvenlafaxine is apparently not affected by diazepam.The pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam, isalso not affected by VENLOR XR.Lithium:Lithium does not affect the steady state pharmacokinetics of VENLOR XR and O-desmethylvenlafaxine. Thepharmacokinetics of lithium is also not affected by VENLOR XR.Imipramine:The pharmacokinetics of imipramine and 2-OH-imipramine is not affected by VENLOR XR. However, theAUC, Cmax and Cmin of desipramine is increased by about 35% when VENLOR XR is co-administered. Thepharmacokinetics of venlafaxine and O-desmethylvenlafaxine are not affected by imipramine. This should beconsidered when imipramine and VENLOR XR are co-administered.Medicines highly bound to plasma proteins:Since only 27% of VENLOR XR is plasma protein bound, the concomitant administration of VENLOR XRand other highly protein bound medicines is not expected to result in increased free concentration of themedicine due to displacement.
Medicines metabolised by cytochrome P450 isoenzymes:VENLOR XR only weakly inhibits CYP2D6. VENLOR XR has no inhibitory effect on CYP3A4, CYP1A2, andCYP2C9 in vitro.
PREGNANCY AND LACTATION:The safety of VENLOR XR in pregnancy and lactation has not been established (see CONTRA-INDICATIONS). If VENLOR XR is used up to shortly before birth, discontinuation effects should beconsidered in the newborn. VENLOR XR use late in the third trimester has led to neonatal complicationsrequiring respiratory support or prolonged hospitalisation.As both venlafaxineand O-desmethylvenlafaxine are excreted in breast milk, a decision should be made as towhether VENLOR XR should be discontinued, or whether the patient should stop breastfeeding.Patients falling pregnant or planning a pregnancy during therapy should inform their doctor.
DOSAGE AND DIRECTIONS FOR USE:The recommended daily dose for VENLOR XR is 75 mg once daily. The dose may be increased to 150 mgonce daily after several weeks if further clinical improvement is required.This dose can be further increased to 225 mg once daily. Intervals of 2 weeks or more, but not less than 4 days,should be allowed between dose increments. In depressed patients the dose may be increased to 375 mg oncedaily. The dose should then be gradually reduced consistent with patient response and tolerance.VENLOR XR should be taken with food. Swallow the capsule whole, with a glass of water. The capsule maynot be chewed, crushed, divided or dissolved.VENLOR XR should be taken once a day at more or less the same time, either in the mornings or at night.The active ingredient is released into the digestive system over an extended period of time.
Patients with renal impairment:Lower doses of VENLOR XR is recommended in patients with renal impairment. In patients with renalimpairment with a glomerular filtration rate (GFR) of 10 - 70 ml/min, the total daily dose of VENLOR XR mustbe reduced by 25 -50 %. In haemodialysis patients, the total daily dose of VENLOR XR must be reduced by50 %. VENLOR XR administration must be withheld during dialysis and only given after completion thereof.Patients with hepatic impairment:In patients with moderate hepatic impairment, the total daily dose of VENLOR XR must be reduced by 50 %.For some patients, reductions of more than 50 % may be appropriate.
Treatment of children and the elderly:Children: See (CONTRA-INDICATIONS).Elderly patients: No dosage adjustments of VENLOR XR are recommended solely based on age.Maintenance, continuation and extended treatment:Periodic reassessment of the need for long-term therapy with VENLOR XR is recommended. It is unknownif the dose of antidepressant needed to induce remission is the same as the dose needed to maintain and/orsustain euthymia.
Discontinuing VENLOR XR:When discontinuation of VENLOR XR therapy is indicated, dose tapering is recommended. If venlafaxine hasbeen used for more than 6 weeks, the tapering period should extend over at least two weeks (see SIDE-EFFECTS AND SPECIAL PRECAUTIONS). The tapering period is influenced by the dose, duration oftherapy and the individual patient. Patients should not discontinue VENLOR XR therapy abruptly withoutconsulting with their doctor (see SIDE-EFFECTS AND SPECIAL PRECAUTIONS).SIDE-EFFECTS AND SPECIAL PRECAUTIONS:Side-effects:Hostility, suicidal ideation and self-harm has been reported in children.
The adverse events most commonly associated with VENLOR XR administration are nervous systemcomplaints, such as headache, dizziness, insomnia, somnolence, nervousness and dry mouth; gastrointestinalcomplaints, including anorexia, nausea and constipation; and abnormal ejaculation/orgasm, sweating andasthenia. Many of the frequently observed adverse events are dose related. With continued therapy, theseadverse events generally decrease in frequency and intensity, and in general do not require discontinuation
of treatment.The following side-effects are frequently ( 1 % patients) reported with the use of VENLOR XR.Haematological and lymphatic system disorders:Frequent: Ecchymosis.Less frequent: Mucous membrane bleeding, prolonged bleeding time,
thrombocytopenia, agranulocytosis, aplastic anaemia,neutropenia and pancytopenia.
Metabolic and nutritional disorders:Frequent: Changes in serum cholesterol (possibly dose related and
after prolonged use), weight loss, and weight gain.Less frequent: Hyponatraemia, abnormal liver function tests, hepatitis,
increased prolactin and syndrome of inappropriateantidiuretic hormone secretion (SIADH).
Neuropsychiatric disorders:Frequent: Agitation, twitching, anxiety, nervousness, confusion,
depersonalisation, depression, amnesia, somnolence,insomnia, abnormal dreams, abnormal thinking, emotionallability, hypertonia, hyperaesthesia, paraesthesia,dizziness, vertigo, decreased libido, tremor, trismus, drymouth, urinary retention and sedation.
Less frequent: Apathy, myoclonus, convulsion, neuroleptic malignantsyndrome, serotonergic syndrome, extrapyramidal signs(e.g. dyskinesia, dystonia), tardive dyskinesia, delirium,hallucinations and manic reaction.
Special senses disorders:Frequent: Abnormality of accommodation, abnormal vision, mydriasis,
taste perversion and tinnitus.
Cardiovascular disorders:Frequent: Vasodilation (mostly flushes) and hypertension.Less frequent: Palpitations, tachycardia, postural hypotension, oedema,
migraine, hypotension, syncope, QT prolongation,ventricular tachycardia and fibrillation.
Respiratory disorders:Frequent: Yawning, dyspnoea, rhinitis, pharyngitis and bronchitis.Less frequent: Pulmonary eosinophilia.
Gastrointestinal disorders:Frequent: Constipation, anorexia, nausea, vomiting, eructation,
dyspepsia, flatulence, and diarrhoea. Dose-related nauseais common at the start of treatment. It decreases over thefirst few weeks of therapy.
Less frequent: Increased appetite, bruxism, and pancreatitis.
Skin and appendages disorders:Frequent: Rash, pruritus and sweating (including night sweats).Less frequent: Alopecia, Stevens-Johnson syndrome and erythema
Musculoskeletal disorders:Frequent: Arthralgia and myalgia.Less frequent: Rhabdomyolysis.
Urogenital disorders:Frequent: Urinary frequency, impotence, anorgasmia, impaired
urination and erectile dysfunction.Less frequent: Abnormal orgasm/ejaculation, menorrhagia and urinary
General disorders:Frequent: Abdominal pain, chest pain, neck pain, back pain, headache,
asthenia and chills.Less frequent: Anaphylaxis and photosensitivity reaction.
As discontinuation effects are known to occur with some antidepressants, it is recommended to taper thedosage of VENLOR XR gradually and to monitor the patient (see DOSAGE AND DIRECTIONS FORUSE). The following adverse effects have been reported after abrupt discontinuation, rapid dose reductionor tapering of treatment: nervousness, confusion, fatigue, insomnia, somnolence or other sleep disturbances,dizziness, paraesthesia, convulsion, headache, vertigo, sweating, tinnitus, dry mouth, anorexia, nausea,vomiting, diarrhoea, agitation, anxiety and hypomania. The majority of these reactions are mild and resolvewithout intervention.
Special Precautions:Suicide is a risk in all depressed patients. To reduce the possibility of overdose, VENLOR XR prescriptionsshould be for the smallest amount of tablets consistent with good patient management.
Caution is advised when VENLOR XR is introduced in patients with a history of seizures. VENLOR XRtherapy should be discontinued in any patient developing a seizure.Should a rash, urticaria, or a related allergic phenomenon develop, the patient should notify their doctorthereof.
In some patients, VENLOR XR treatment may result in an increase in blood pressure. Reports on the effectson supine diastolic blood pressure show mean increases of approximately 2 mmHg. Patients with treatedhypertension or elevated blood pressure at the onset of VENLOR XR therapy is not predisposed tofurther rises in blood pressure. Blood pressure monitoring may be advisable inpatients treated with doses greater than 200 mg/day. A reduction in the dose, or discontinuation should beconsidered if patients experience a sustained increase in blood pressure while receivingVENLOR XR.Mania/hypomania activation has been reported. As is the case with all antidepressants, VENLOR XR shouldbe used cautiously in patients with a history of mania.
Venlafaxine treatment is frequently associated with loss of appetite. Dose-related weight loss has also beenreported. Therefore, a significant decrease in body weight, especially in already underweight depressedpatients, may be an unwanted effect of treatment with venlafaxine. Weight gain is less frequently associatedwith venlafaxine treatment.
Patients taking VENLOR XR over long periods of time show no signs of drug-seeking behaviour, developmentof tolerance, or dose escalation. Doctors are nevertheless advised to carefully evaluate patients for a historyof drug abuse, to monitor such patients closely and screen them for signs of misuse or abuse of VENLORXR (e.g. drug-seeking behaviour, increase in dose or development of tolerance).Since the clinical experience with VENLOR XR in patients with concomitant systemic illnesses is limited,care should be taken when VENLOR XR is administered to patients with diseases or conditions affectinghaemodynamic responses or metabolism.
The effects of VENLOR XR in patients with a recent history of myocardial infarction or unstable heart diseasehave not been evaluated to any appreciable extent. Treatment with VENLOR XR does not result in any seriousarrhythmias and mean PR, QRS, or QT intervals are not significantly prolonged.
Treatment is associated with an approximate increase of 4 beats/minute in mean heart rate. Care shouldtherefore be taken when VENLOR XR is prescribed to patients whose underlying medical conditions might
be compromised by increases in heart rate (e.g. patients with hyperthyroidism, heart failure, or recent myocardialinfarction).
Care should be taken when VENLOR XR is administered to patients with moderate to severe renal impairmentor cirrhosis of the liver. A lower dose or the frequency of dosing may be considered (see DOSAGE ANDDIRECTIONS FOR USE).The use of VENLOR XR may be associated with impairment of judgement, thinking or motor skills. Until theadverse effect profile of the medication has been established in a patient, patients should be advised not tooperate hazardous machinery or not to drive.
Sudden discontinuation of VENLOR XR therapy can result in discontinuation effects (see Side-effects).Serum cholesterol increases have been reported in patients treated for at least 3 months. During long-termtreatment, serum cholesterol measurement should be considered.
The risk of cutaneous or mucous membrane bleeding may be increased. VENLOR XR should therefore beused with care in patients predisposed to bleeding from these sites.
Hyponatraemia and/or the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have beenreported with VENLOR XR. These adverse reactions usually occurred in dehydrated or elderly patients orthose on diuretics.
As mydriasis has been associated with VENLOR XR, patients at risk for acute narrow angle glaucoma orwith raised intra-ocular pressure should be closely monitored.
Use in elderly patients:The use of VENLOR XR in healthy elderly patients does not pose exceptional safety problems. Although age-related clinical circumstances, such as renal impairment, may warrant a dose reduction in the elderly, advancedage is not an indication for dosage adjustments per se.
Carcinogenesis, mutagenesis, impairment of fertility:Non-clinical toxicology studies have shown no evidence of the above.
Paediatric use:There is no safety and efficacy data on the use of venlafaxine in children younger than 18 years. Clinical trialsin major depressive disorder, show increases in hostility and suicide-related adverse events such as suicidalideation and self-harm (see CONTRA-INDICATIONS).KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:The most commonly reported symptom is somnolence. The occurrence of generalised convulsions has beenreported.
The recommended treatment of an overdose should be supportive and symptomatic, including the monitoringof vital signs and cardiac rhythm. Consider using activated charcoal and/or a gastric lavage. There are noknown specific antidotes for VENLOR XR.IDENTIFICATION:VENLOR XR 37.5 CAPSULES: White to off-white pellets filled in hard gelatin capsule shells size 3 withorange cap and clear transparent body.VENLOR XR 75 CAPSULES: White to off-white pellets filled in hard gelatin capsule shells size 1 withyellow cap and clear transparent body.VENLOR XR 150 CAPSULES: White to off-white pellets filled in hard gelatin capsule shells size 0 withbuff cap and clear transparent body.
PRESENTATION:VENLOR XR 37.5 CAPSULES: Aluminium foil blister strips of 10 capsules, packed in 30s.VENLOR XR 75 CAPSULES: Aluminium foil blister strips of 10 capsules, packed in 30s.VENLOR XR 150 CAPSULES: Aluminium foil blister strips of 10 capsules, packed in 30s.STORAGE INSTRUCTIONS:Store below 25C. Keep the blister strips in the outer carton until required for use.KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBERS:VENLOR XR 37.5: A40/1.2/0032VENLOR XR 75: A40/1.2/0033VENLOR XR 150: A40/1.2/0034NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:CIPLA MEDPRO (PTY) LTDRosen Heights, Pasita Street,Rosen Park, Bellville, 7530, RSA.
DATE OF PUBLICATION OF THIS PACKAGE INSERT:May 2006.
CIPLA MEDPRO (PTY) LTD