Biofexor

Extended-Release Capsules

Composition :

     Each Extended-Release Capsules contains:       

            37.5 mg , 75 mg , or 150 mg venlafaxine as  venlafaxine hydrochloride

Mechanism of Action

The mechanism of venlafaxine’s antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of serotonin and noradrenaline reuptake

Venlafaxine also weakly inhibits of dopamine reuptake. Studies show that  Venlafaxine and ODV reduce b-adrenergic responsiveness after both acute ( single dose) and chronic administration. venlafaxine and ODV are very similar with respect to their overall action on neurotransmitter  reuptake .

venlafaxine has virtually no affinity for muscarinic cholinergic, H ₁ -histaminergic, or (alpha) ₁ -adrenergic receptors in vitro. Pharmacologic activity at these receptors may be related to various side effects seen with other antidepressant drugs, such as anticholinergic, sedative, and cardiovascular side 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. It has no significant CNS stimulant activity in rodents . In primate drug discrimination studies , venlafaxine showed no significant stimulant or depressant abuse liability.  

Pharmacokinetics :

at least 92% of a single oral dose of venlafaxine is absorbed after administration of Biofexor , 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 is slower than its rate of elimination . Therefore, the apparent elimination half-life of venlafaxine following administration of Biofexor capsules (15 ± 6 hours) .

Venlafaxine undergoes extensive first-pass metabolism in the liver . Venlafaxine and its metabolites are excreted primarily through the kidneys . Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine, unconjugated ODV, conjugated ODV, or other minor metabolites. 

Administration  of Biofexor 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  , No accumulation of  venlafaxine  or ODV has been observed during chronic administration

Indications:

venlafaxine hydrochloride is indicated for the treatment of depressive illness , including depression accompanied by anxiety .  

Contraindications:

• Known or suspected pregnancy .
• Insufficient data are available to support the use of Biofexor in lactating women. Therefore, such use is contra-indicated.
• Known hypersensitivity to venlafaxine hydrochloride or to any other component of the product. .
• Concomitant use of  venlafaxine  with monoamine oxidase inhibitors .
• Paediatric Use-Safety and effectiveness  in individuals below 18 years of age have not been established , and such use is not recommended .

 

 

 

Side effects :

The most commonly observed adverse events associated with the use of venlafaxine in clinical trials, were : nausea,  insomnia, dry mouth, somnolence, dizziness, constipation , sweating,  nervousness, asthenia and abnormal ejaculation/ orgasm.  .

Other adverse events occurring in at least 3 % of patients were: anorexia, abnormal vision / accommodation , impotence, vomiting, tremor, abnormal dreams, vasodilatation, hypertension, rash, agitation, hypertonia and paraesthesia .

The occurrence of most of these adverse events was dose-related, and the majority of them decreased in intensity and frequency over time. They generally did not lead to cessation of treatment .

In clinical studies the incidence of nausea was lower, and the adaptation to nausea appeared to be  improved with BIOFEXOR. 

Lab. effects : 

• Reversible increases in liver enzymes were seen during clinical trials in a small number of patients (0.5 %) treated with venlafaxine .
• Alteration in serum cholesterol are seen in some patients treated with venlafaxine .
• Cases of hyponatraemia have been reported rarely with venlafaxine , usually in the elderly, which have resolved on discontinuation of the drug .

Pregnancy and lactation:

The use of Biofexor during Known or suspected pregnancy is contra-indicated. Patients should be advised to notify their physician if they become pregnant, or intend to become pregnant during therapy .

In preclinical studies, Venlafaxine and ODV were found to pass into maternal milk. Therefore, such use is contra-indicated.

Effects on ability to Drive and Use Machines:

Any psychoactive drug may impair judgement, thinking or motor skills. Therefore , patients should be cautioned about their ability to drive or operate hazardous machinery .

Precautions :

Women of childbearing potential should employ adequate contraception whilst taking Biofexor.

Patients being treated with antidepressants should be observed closely for clinical worsening and  suicidality, especially at the beginning of a course of drug therapy, or at times of dose changes, either increases or decreases.

In clinical trials with venlafaxine , seizures were reported in .02 % of all venlafaxine-treated patients. All patients recovered. No seizures occurred in venlafaxine-treated patients during clinical trials. However, as with all antidepressants, Biofexor should be introduced with care in patients with in history of seizure and should be discontinued in any patient who develops seizures .

During clinical trials , rash developed in 3 % of patients treated with venlafaxine. Patients should be advised to notify their physician if they develop a rash , urticaria or related allergic phenomenon.

The clearances of venlafaxine and its active metabolite are decreased and half-lives increased in patients with moderate to severe renal impairment or cirrhosis of the liver . Therefore, Biofexor should be used with caution in these patients.

Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of  myocardial infarction or unstable heart disease. Therefore, it should be used with caution in these patients.

Clinically significant changes in PR, QRS, or QTC intervals were rarely observed in patients treated with venlafaxine during clinical trials.

Increased in blood pressure have been reported in patients treated with high doses of venlafaxine .Blood pressure monitoring is advisable in patients receiving daily dose of >200 mg .

Drug interactions :

Adverse reaction, 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 .

 

Do not use Biofexor in combination with an MAOI , or within at least 14 days of discontinuing MAOI treatment . Allow at least 7 days after stopping BIOFEXOR before starting an MAOI .

The risk of using venlafaxine  in combination with other CNS – active drugs has not been systematically evaluated , except in the case of lithium, imipramine and diazepam. Caution is advised if the concomitant administration of Biofexor and other CNS – active drugs is required .

Venlafaxine had no effect on the pharmacokinetic profiles of diazepam, lithium , or ethanol, and  did not affect the psychomotor and psychometric effects iduced by diazepam or ethanol .

Venlafaxine did not affect the hepatic metabolism of the tricyclic antidepressant, imipramine  or its active metabolite, desipramine. However, the renal clearance of 2-hydroxy desipramine was reduced with coadministration . Imipramine partially inhibited the formation of ODV. However, no dosage adjustment of either drug is necessary when Biofexor and imipramine are given concomitantly .

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 quantities in the systemic circulation. Therefore, no dosage adjustment seems necessary when Biofexor is coadministered with cimetidine .For elderly patients, or patients with hepatic dysfunction ,the interaction could potentially be more pronounced ,and for such patients,clinical monitoring is indicated when Biofexor is administered with cimetidine .

Venlafaxine is primarily metabolized to its equally active metabolite, ODV, by the cytochrome P450 enzyme CYP2D6 However, unlike many other antidepressants, no dosage adjustment is necessary when Biofexor is administered concomitantly with drugs which inhibit CYP2D6, or when used in patients who are poor CYP2D6 metabolisers, since the total concentration of active compound (Venlafaxine and ODV ) is not affected.

Venlafaxine is a relatively weak inhibitor of  CYP2D6 , and does not inhibit CYP1A2, CYP2C9  or CYP3A4 Therefore, Biofexor is not expected to interact with other drugs metabolized by these hepatic enzymes.

The major elimination pathways for venlafaxine are through  CYP2D6 and CYP3A4 .Therefore, caution should be used with concomitant intake of drugs which inhibit both of these enzymes . Such interactions have not been studied to date.

Venlafaxine and ODV are 27 % and 30 % bound to plasma proteins. Therefore, drug interactions due to protein  binding of venlafaxine and  the major metabolite are not expected .

There is no evidence suggesting incompatibility  between treatment with venlafaxine and treatment with either antihypertensives ( including b-blockers, ACE inhibitors and diuretics ) or hypoglycaemic agents . 

There are no clinical studies to evaluate the benefit of combined use of Biofexor with another antidepressant or electroconvulsive therapy (ECT) .

Overdose:

Paraesthesia in limbs. Sinus and ventricular tachycardia, bradycardia and seizures have been observed in association with overdosage of  venlafaxine , either alone or in combination with other drugs and / or alcohol . Such events are rare and usually resolve spontaneously .

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

The haemodialysis  clearance of venlafaxine  and its main metabolite, ODV , are low. Therefore, they are not considered dialyzable .

DOSAGE AND ADMINISTRATION :

The recommended dose for Biofexor is 75 mg once daily . If after 2 weeks further clinical improvement is required, the dose  may be increased to 150 mg once daily . If needed, the  dose can be further increased up to 225 mg once daily . Dose increments should be made at intervals of approximately 2 weeks or more , but not less than 4 days . Antidepressant activity with 75 mg dose was observed after 2 weeks of treatment . 

Biofexor should be taken with food. Each capsule should be swallowed whole with fluid . Do not divide , crush , chew, or place the capsule in water . Biofexor should be administered once daily , at approximately the same time , either in the morning or in the evening . 

Patients with Renal or Hepatic Impairment

The half-lives for both venlafaxine and ODV are increased in patients with renal and hepatic impairment

For patients with mild  renal impairment (GFR>30 mL/min)  or mild  hepatic impairment , no change in dosage is necessary .

For patients with moderate renal impairment (GFR10-30 mL/min)  or moderate  hepatic impairment , the dose should be reduced by 50 % .

Elderly Patients

No adjustment form the usual dosage is recommended for elderly patients. However, as with any therapy, caution should be exercised in treating the elderly ( e.g. due to the possibility of renal impairment ) .The lowest effective dose should always be used, and patients should be carefully monitored when an increase in the dose is required . 

Paediatric Use

Safety and effectiveness  in individuals below 18 years of age have not been established , and such use is not recommended .

Maintenance/ Continuation / Extended Treatment

The physician should periodically re-evaluate the usefulness of long-term Biofexor treatment for the individual patient. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy .

Venlafaxine has been shown to be efficacious during long-term ( up to 12 months ) treatment .

Discontinuing Biofexor

Discontinuation effects are well known to occur with the abrupt withdrawal of other antidepressants. While the discontinuation effects of Biofexor have not been systematically evaluated in controlled clinical trials , a retrospective survey of events occurring during taper or following discontinuation of Biofexor revealed the following events that occurred with an incidence of at least 3 % and at least twice the placebo incidence : dizziness, dry mouth, insomnia, nausea, nervousness and sweating .

The period required for discontinuation may depend on the dose, duration of therapy and the individual patient.

PRESENTATION :

20 Extended-Release Capsules of 37.5 mg , 75 mg , or 150 mg venlafaxine as  venlafaxine hydrochloride.