SINEPIN Capsule Ref.[7922] Active ingredients: Doxepin

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an associated with an increased risk of suicidal thoughts, self harm and suicide (suicide related events). This risk persists until significant remission occurs. As improvement many not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared with placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

The once-a-day dosage regimen of Doxepin 25mg Capsules in patients with intercurrent illness or patients taking other medications should be carefully adjusted. This is especially important in patients receiving other medications with anticholinergic effects.

The use of Doxepin 25mg Capsules on a once-a-day dosage regimen in geriatric patients should be adjusted carefully on the basis of the patient’s condition. The elderly are particularly liable to experience toxic effects, especially agitation, confusion and postural hypotension. The initial dose should be increased with caution under close supervision. Half the normal maintenance dose may be sufficient to produce a satisfactory clinical response.

Patients should be warned that drowsiness may occur with the use of Doxepin 25mg Capsules. Patients should also be cautioned that their response to alcohol may be potentiated.

Although Doxepin 25mg Capsules carry less risk than other tricyclic anti-depressants, caution should be observed in the treatment of patients with severe cardiovascular disease, including patients with heart block, cardiac arrhythmia and those who have experienced a recent myocardial infarction.

Serotonin syndrome

Concomitant administration of Doxepin 25mg Capsules and buprenorphine/opioids may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).

If concomitant treatment of buprenorphine/opioids is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Hepatic/renal impairment

Use with caution in patients with hepatic and/or renal impairment.

Patients with epilepsy

Use with caution in patients with a history of epilepsy.

Since suicide is an inherent risk in any depressed patient until significant improvement has occurred, patients should be closely supervised during early therapy.

Patients with benign prostatic hyperplasia may experience an increase in associated urinary retention (see ‘Undesirable effects’).

Doxepin 25mg Capsule contains lactose

Patients with rare hereditary problems of fructose intolerance, galactose intolerance, galactosaemia or glucosegalactose malabsorption should not take this medicine.

Doxepin, like other tricyclic antidepressants (TCAs), is metabolised by cytochrome P450 (CYP) 2D6. Inhibitors or substrates of CYP2D6 (e.g. quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of TCAs when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6 and the therapeutic index of the TCA. The clinical significance of this interaction with doxepin has not been systematically evaluated.

Combined use with other anti-depressants, alcohol or anti-anxiety agents should be undertaken with due recognition of the possibility of potentiation. It is known, for example, that monoamine oxidase inhibitors may potentiate other drug effects, therefore Doxepin 25mg Capsules should not be given concurrently, or within two weeks of cessation of therapy, with monoamine oxidase inhibitors.

Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of doxepin.

Doxepin should not be given with sympathomimetic agents such as ephedrine, isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine.

General anaesthetics and local anaesthetics (containing sympathomimetics) given during tricyclic or tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension, or hypertension. If surgery is necessary, the anaesthetist should be informed that a patient is being so treated.

Doxepin may decrease the anti-hypertensive effect of agents such as debrisoquine, bethanidine, guanethidine and possibly clonidine. It usually requires daily doses of doxepin in excess of 150mg before any effect on the action of guanethidine is seen. It would be advisable to review all anti-hypertensive therapy during treatment with tricyclic antidepressants.

Barbiturates may increase the rate of metabolism of doxepin.

Doxepin 25mg Capsules may reduce the effect of sublingual nitrates owing to dry mouth.

The dose of thyroid hormone medication may need reducing if Doxepin 25mg Capsules are being given concurrently.

Doxepin 25mg Capsules should be used cautiously when co-administered with:

• Buprenorphine/opioids as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).

Doxepin crosses the placenta. Reproduction studies have been performed in rats, rabbits and monkeys and there was no evidence of harm to the animal foetus. The relevance to humans is not known. Since there is insufficient experience in pregnant women who have received this drug, its safety in pregnancy has not been established.

Breast-feeding

Doxepin and its active metabolite desmethyldoxepin are excreted in breast milk. There has been a report of apnoea and drowsiness occurring in a nursing infant whose mother was taking doxepin. The use of Doxepin 25mg Capsules is contraindicated during lactation.

Since drowsiness may occur with the use of Doxepin 25mg Capsules, patients should be warned of the possibility and cautioned against driving a car or operating machinery while taking this drug.

Frequency is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Note: Some of the side-effects noted below have not been specifically reported with Doxepin 25mg Capsules. However, due to the close pharmacological similarities amongst the tricyclics, the reactions should be considered when prescribing Doxepin 25mg Capsules.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

None known.