Agoviz

Agoviz is structurally closely related to melatonin. Agoviz is a potent agonist at melatonin receptors and an antagonist at serotonin-2C (5-HT2C) receptors, tested in an animal model of depression. Agoviz was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continue to develop the drug and conduct phase III trials in the European Union. In 2005 Servier submitted Agoviz to the European Medicines Agency (EMEA). On 27 July 2006 the Committee for Medical Products for Human Use (CHMP) of the EMEA recommended a refusal of the marketing authorisation of Agoviz/Thymanax. The major concern was that efficacy had not been sufficiently shown. In 2006 Servier sold the rights to develop Agoviz in the US to Novartis. The development for the US market was discontinued in October 2011. It is currently sold in Australia under the Agoviz trade name.

Agoviz is indicated for the treatment of major depressive episodes in adults.

Recommended Dose: 25 mg once daily taken orally at bedtime.

After 2 weeks of treatment, if there is no improvement of symptoms, the dose may be increased to 50 mg once daily, i.e. two 25 mg tab, taken together at bedtime.

Decision of dose increase has to be balanced with a higher risk of transaminases elevation. Any dose increase to 50 mg should be made on an individual patient benefit/risk basis and with strict respect of liver function test (LFT) monitoring.

Liver function tests should be performed in all patients before starting treatment. Treatment should not be initiated if transaminases exceed 3 X upper limit of normal. During treatment transaminases should be monitored periodically after around three weeks, six weeks (end of acute phase), twelve weeks and twenty four weeks (end of maintenance phase) and thereafter when clinically indicated. Treatment should be discontinued if transaminases exceed 3 X upper limit of normal.

Treatment Duration: Patients with depression should be treated for a sufficient period of at least 6 months to ensure free of symptoms.

Switching Therapy from SSRI/SNRI Antidepressant to Agoviz: Patients may experience discontinuation symptoms after cessation from an SSRI/SNRI antidepressant.

The SmPC of the actual SSRI/SNRI should be consulted on how to withdraw the treatment to avoid this. Agoviz can be started immediately while tapering the dosage of a SSRI/SNRI.

Treatment Discontinuation: No dosage tapering is needed on treatment discontinuation.

Special Populations: Elderly: The efficacy and safety of Agoviz (25 to 50 mg/day) have been established in elderly depressed patients (<75 years). No effect is documented in patients ≥75 years. Therefore Agoviz should not be used by patients in this age group. No dose adjustment is required in relation to age.

Renal Impairment: No relevant modification in Agoviz pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on the use of Agoviz in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing Agoviz to these patients.

Hepatic Impairment: Agoviz is contraindicated in patients with hepatic impairment.

Paediatric Population: The safety and efficacy of Agoviz in children from 2 years onwards for treatment of major depressive episodes have not yet been established. No data are available. There is no relevant use of Agoviz in children from birth to 2 years for treatment of major depressive episodes.

Administration: For oral use.

Agoviz film-coated tablets may be taken with or without food.

Hypersensitivity to Agoviz or to any of the excipients of Agoviz.

Hepatic impairment (ie, cirrhosis or active liver disease).

Concomitant use of potent CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin).

Potential Interactions Affecting Agoviz: Agoviz is metabolised mainly by cytochrome P450 (CYP450) 1A2 (CYP1A2) (90%) and by CYP2C9/19 (10%). Medicinal products that interact with these isoenzymes may decrease or increase the bioavailability of Agoviz.

Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor markedly inhibits the metabolism of Agoviz resulting in a 60-fold (range 12-412) increase of Agoviz exposure. Consequently, co-administration of Agoviz with potent CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) is contraindicated.

Combination of Agoviz with oestrogens (moderate CYP1A2 inhibitors) results in a several fold increased exposure of Agoviz. While there was no specific safety signal in the 800 patients treated in combination with oestrogens, caution should be exercised when prescribing Agoviz with other moderate CYP1A2 inhibitors (eg, propranolol, enoxacin) until more experience has been gained.

Rifampicin an inducer of all 3 cytochromes involved in the metabolism of Agoviz may decrease the bioavailability of Agoviz.

Smoking induces CYP1A2 and has been shown to decrease the bioavailability of Agoviz, especially in heavy smokers (>15 cigarettes/day).

Potential for Agoviz to Affect Other Medicinal Products: In vivo, Agoviz does not induce CYP450 isoenzymes. Agoviz inhibits neither CYP1A2 in vivo nor the other CYP450 in vitro. Therefore, Agoviz will not modify exposure to medicinal products metabolised by CYP450.

Medicinal Products Highly Bound to Plasma Protein: Agoviz does not modify free concentrations of medicinal products highly bound to plasma proteins or vice versa.

Other Medicinal Products: No evidence of pharmacokinetic or pharmacodynamic interaction with medicinal products which could be prescribed concomitantly with Agoviz in the target population was found in phase I clinical trials: Benzodiazepines, lithium, paroxetine, fluconazole and theophylline.

Alcohol: The combination of Agoviz and alcohol is not advisable.

Electroconvulsive Therapy (ECT): There is no experience of concurrent use of Agoviz with ECT. Animal studies have not shown proconvulsant properties. Therefore, clinical consequences of ECT concomitant treatment with Agoviz are considered to be unlikely.

Paediatric Population: Interaction studies have only been performed in adults.

In clinical trials, >7200 depressed patients have received Agoviz.

Adverse reactions were usually mild or moderate and occurred within the first 2 weeks of treatment.

The most common adverse reactions were nausea and dizziness.

These adverse reactions were usually transient and did not generally lead to cessation of therapy.

Depressed patients display a number of symptoms that are associated with the illness itself. It is therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which are a result of treatment with Agoviz.

Adverse reactions are listed as follows using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data). The frequencies have not been corrected for placebo.

Nervous System Disorders: Common: Headache, dizziness, somnolence, insomnia, migraine. Uncommon: Paraesthesia.

Psychiatric Disorders: Common: Anxiety. Uncommon: Agitation and related symptoms* (eg, irritability and restlessness), aggression*, nightmares*, abnormal dreams*. Rare: Mania/ hypomania*. These symptoms may also be due to the underlying disease. Hallucinations*.

Frequency Not Known: Suicidal thoughts or behavior.

Eye Disorders: Uncommon: Blurred vision.

Gastrointestinal Disorders: Common: Nausea, diarrhoea, constipation, abdominal pain, vomiting*.

Skin and Subcutaneous Tissue Disorders: Common: Hyperhidrosis. Uncommon: Eczema, pruritus*. Rare: Erythematous rash.

Musculoskeletal and Connective Tissue Disorders: Common: Back pain.

General Disorders and Administration Site Conditions: Common: Fatigue.

Hepatobiliary Disorders: Common: Increased ALAT and/or ASAT (in clinical studies, increases >3 times the ULN range in ALAT and/or ASAT in 1.4% of patients on Agoviz 25 mg daily and 2.5% on Agoviz 50 mg daily vs 0.6% on palcebo). Rare: Hepatitis, increased γ-glutamyltransferase* (GGT) (>3 times the ULN range), increased alkaline phosphatase* (>3 times the ULN range), hepatic failure*, jaundice*.

Investigations: Rare: Increased weight*, decreased weight*.

*Frequency estimated from clinical trials for adverse events detected from spontaneous report.