Deseril Tablets 1mg

1. Name Of The Medicinal Product

Deseril^® tablets 1mg

2. Qualitative And Quantitative Composition

Methysergide maleate BP 1.33 mg.

3. Pharmaceutical Form

White, biconvex, sugar-coated tablet, branded DSL on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Prophylactic treatment of migraine with or without aura, and cluster headache and other vascular headaches in patients who, despite attempts at control, experience headaches of such severity or regularity that social or economic life is seriously disrupted. (Note: Deseril is not recommended for treatment of the acute attack).

Diarrhoea caused by carcinoid disease.

4.2 Posology And Method Of Administration

Prophylactic treatment of headache: 1 or 2 tablets three times a day with meals. Treatment should start with one tablet at bedtime and dosage should then be increased gradually over about two weeks until effective levels are reached. The minimum effective dose should be used, often that which will prevent 75% of attacks rather than all headaches.

From the outset, patients should understand that regular clinical supervision and periodic withdrawal of treatment are essential so that adverse effects can be recognised and minimised (see Section 4.4 Special warnings and precautions for use).

Carcinoid Syndrome: High doses are usually necessary. In most reported cases, dosage ranged between 12 and 20 tablets daily.

Children: Not recommended.

Elderly: No evidence exists that elderly patients require different dosage from younger patients.

4.3 Contraindications

Hypersensitivity to methysergide or any of the excipients of Deseril, pregnancy, lactation, peripheral vascular disorders, progressive arteriosclerosis, inadequately controlled hypertension, coronary heart disease, valvular heart disease, phlebitis or cellulitis of the lower extremities, impaired kidney or liver function, temporal arteritis, hemiplegic or basilar migraine, history of drug – induced fibrotic disorders (e.g. retroperitoneal fibrosis), pulmonary fibrosis, collagen diseases, obstructive diseases of the urinary tract, cachectic or septic conditions.

Concomitant treatment with macrolide antibiotics, HIV-protease or reverse-transcriptase inhibitors, azole antifungals (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Concomitant treatment with vasoconstrictive agents (including ergot alkaloids), sumatriptan and other 5HT₁-receptor agonists (see section 4.5 Interaction with other medicinal products and other forms of interaction).

4.4 Special Warnings And Precautions For Use

Continuous Deseril administration should not exceed six months without a drug-free interval of at least one month for re-assessment; dosage should be reduced gradually over two to three weeks to avoid rebound headaches. In patients undergoing treatment with Deseril the dose of ergotamine required to control acute attacks may have to be reduced.

Regular clinical supervision of patients treated with Deseril is essential. Particular attention should be paid to complaints of urinary dysfunction, pain in the loin, flank or chest, and pain, coldness or numbness in the limbs. Patients should be regularly examined for the presence of cardiac murmurs, vascular bruits, pleural or pericardial friction rubs and abdominal or flank masses or tenderness. Caution is also advised during drug administration to patients with a past history of peptic ulceration.

At the first signs of impaired peripheral circulation, prompt withdrawal of the drug is recommended.

In carcinoid syndrome the risk of adverse reactions due to the higher dosage must be weighed against the therapeutic benefit.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of Deseril and vasoconstrictors or vasopressors, including ergot alkaloids, sumatriptan and other 5-HT₁-receptor agonists, and nicotine (e.g. heavy smoking) must be avoided since this may result in enhanced vasoconstriction (see section 4.3 Contra-indications). Methysergide should not be administered within six hours of therapy with 5-HT₁ receptor agonists. In addition, use of 5-HT₁ receptor agonists should be avoided for at least 24 hours after the last methysergide dose.

The concomitant use of cytochrome P450 3A (CYP3A) inhibitors such as macrolide antibiotics (e.g. troleandomycin, erythromycin, clarithromycin), HIV protease or reverse transcriptase inhibitors (e.g. ritonavir, indinavir, nelfinavir, delavirdine), azole antifungals (e.g. ketoconazole, itraconazole, voriconazole) or cimetidine and Deseril must be avoided (see 4.3 Contra-indications), since this can result in an elevated exposure to methysergide and ergot toxicity (vasospasm and ischemia of the extremities and other tissues). Ergot alkaloids have also been shown to be inhibitors of CYP3A. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

4.6 Pregnancy And Lactation

Deseril is contra-indicated during pregnancy. It is likely that methysergide is excreted in breast milk. Deseril is therefore contra-indicated for nursing mothers.

4.7 Effects On Ability To Drive And Use Machines

Patients should be warned of the potential hazards of driving or operating machinery if they experience side effects such as dizziness, drowsiness or disturbances in vision.

4.8 Undesirable Effects

General: The most commonly reported side-effects are nausea, heartburn, abdominal discomfort, vomiting, dizziness, lassitude and drowsiness. These side-effects can often be minimised by taking Deseril with food. Tissue oedema, insomnia, vertigo, leg cramps and weight gain have occurred, and skin eruptions or loss of scalp hair have occasionally been reported. Mental and behavioural disturbances have occurred in isolated instances.

Fibrosis: Continuous long-term Deseril administration has been associated with the development of fibrosis particularly of the pleura and retroperitoneum but, in rare cases also of the pericardium and the cardiac valves.

Retroperitoneal fibrosis: May present with symptoms of urinary tract obstruction such as general malaise, backache, persistent loin or flank pain, oliguria, dysuria, increased blood nitrogen and vascular insufficiency of the lower limbs. Deseril must be withdrawn if retroperitoneal fibrosis develops; drug withdrawal is often associated with clinical improvement over a few days to several weeks.

Fibrosis in other areas: Fibrotic processes involving lungs, pleura, heart valves and major vessels have been reported. Fibrosis of the pericardium and cardiac valves is very rare when the drug was given for less than 6 months. Pleuro-pulmonary fibrosis may present with chest pain, dyspnoea or pleural friction rub and pleural effusion. Cardiac valve fibrosis may be noticed by cardiac murmurs, which may lead to impaired cardiac function. Appearance of these symptoms demands immediate withdrawal of Deseril. These fibrotic manifestations are often reversible although less readily so than retroperitoneal fibrosis.

Vascular: Vascular reactions, (affecting both large and small arteries) including arterial spasm, have been seen in some patients. The following have all been described; arterial spasm in a limb causing coldness, numbness, pain or intermittent claudication with or without paraesthesia and diminished or absent pulse; renal artery spasm giving rise to transitory hypertension; mesenteric artery spasm causing abdominal pain; retinal artery spasm causing reversible loss of vision; coronary artery spasm causing angina. Arterial spasm is rapidly reversible following drug withdrawal. There have been isolated reports of myocardial infarction particularly in patients not adhering to the contraindications of coronary heart disease or the use of other vasoconstrictive drugs.

4.9 Overdose

Experience with cases of overdoses with Deseril is limited. Symptoms: headache, agitation, hyperactivity, nausea, vomiting, abdominal pain, mydriasis, tachycardia, cyanosis, peripheral vasospasm with diminished pulses and coldness of extremities.

Treatment: Treatment is essentially symptomatic and supportive. Administration of activated charcoal is recommended; in case of very recent intake, gastric lavage may be considered. For controlling hyperactivity, conventional sedative measures may be used. In the event of severe vasospastic reactions, i.v. administration of a peripheral vasodilator such as nitroprusside, phentolamine, local administration of warmth to the affected area and nursing care to prevent tissue damage are recommended. In the case of coronary constriction, appropriate treatment should be initiated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Deseril is effective in the prevention of migraine chiefly on account of its marked 5–HT receptor antagonism, probably by inhibition of 5-HT_2B receptors (inhibition of pain-facilitating and permeability-increasing actions of 5-HT).

5.2 Pharmacokinetic Properties

Methysergide is rapidly and well absorbed. The parent drug is metabolised in the liver mainly to methylergometrine. Unchanged parent drug and metabolites are excreted predominantly via the kidney; the elimination is biphasic, with a half-life of 2.7 hours for the α-phase and 10 hours for the β-phase. Protein binding is moderate (66%).

5.3 Preclinical Safety Data

There are no findings of relevance to the prescriber which are additional to those already included in other sections of the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maleic acid, gelatin, stearic acid, talc, maize starch, lactose. The coating constituents are gum acacia, sugar, talc, titanium dioxide, silica, carnauba wax and printing ink (consisting of Shellac, black iron oxide, ethanol and isopropanol).

6.2 Incompatibilities

None.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Aluminium/PVdC blister strips of 60 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

Administrative Data

7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

8. Marketing Authorisation Number(S)

PL16853/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

25 June 1998

10. Date Of Revision Of The Text

December 2006

11. Legal status

POM

Alliance, Alliance Pharmaceuticals and associated devices are registered Trademarks of Alliance Pharmaceuticals Ltd.