Almitrine Bismesylate + Raubasine

Approved Indications:

• Chronic Cerebrovascular Insufficiency
  Indicated for the treatment of symptoms related to cerebral hypoperfusion, such as memory decline, lack of concentration, mood instability, vertigo, and dizziness, particularly in elderly patients or those with post-stroke sequelae.
• Peripheral Arterial Disease (PAD)
  Used in the management of symptoms related to chronic peripheral circulatory insufficiency, including cold extremities, leg pain during walking (intermittent claudication), and tissue ischemia.

Clinically Accepted Off-Label Use:

• Chronic Hypoxemia in COPD
  Almitrine component may be used to improve arterial oxygenation by enhancing ventilation-perfusion matching in chronic obstructive pulmonary disease, particularly in patients with severe resting hypoxemia.

Adults:

• Recommended dose: 1 tablet containing Almitrine Bismesylate 30 mg + Raubasine 10 mg, taken twice daily.
• Tablets should be taken orally, after meals, with a glass of water.

Elderly:

• Same as adult dosing; however, patients should be monitored closely for neurological and cardiovascular adverse effects.

Pediatrics:

• Not recommended due to lack of clinical safety and efficacy data in children.

Renal Impairment:

• No established dosage adjustment. Use cautiously, with clinical monitoring.

Hepatic Impairment:

• Contraindicated in severe hepatic dysfunction. In mild-to-moderate cases, use cautiously and monitor liver function periodically.

Duration of Therapy:

• Treatment duration should not exceed 3 consecutive months to reduce the risk of peripheral neuropathy. If symptoms persist, reassessment is advised.

Administration Route:

• Oral (by mouth) only.

Almitrine Bismesylate is a peripheral respiratory stimulant that acts on carotid body chemoreceptors, enhancing alveolar ventilation and oxygen uptake without increasing carbon dioxide elimination. It induces selective pulmonary vasoconstriction in poorly ventilated areas of the lung, improving ventilation-perfusion ratio and systemic oxygenation.

Raubasine, a derivative of the indole alkaloid yohimbine, acts as a cerebral and peripheral vasodilator. It exerts alpha-adrenergic antagonistic effects, reducing vascular resistance, and improving blood flow in ischemic brain and limb tissues. Its vasodilatory action enhances the oxygen delivery promoted by Almitrine.

Together, the combination improves both oxygen availability and blood supply to tissues affected by chronic ischemia or hypoxia.

Almitrine Bismesylate:

• Absorption: Well absorbed orally; peak plasma levels in 1–3 hours.
• Distribution: Extensive tissue binding; plasma protein binding >95%.
• Metabolism: Hepatically metabolized, likely via CYP3A4-mediated oxidation.
• Half-life: Approx. 30 hours.
• Excretion: Predominantly fecal (via bile); minor renal clearance.

Raubasine:

• Absorption: Rapid gastrointestinal absorption.
• Distribution: Widely distributed, including into CNS and vascular tissue.
• Metabolism: Primarily hepatic metabolism; enzymatic pathways not well-defined.
• Half-life: Approx. 5–8 hours.
• Excretion: Mainly renal excretion in metabolized form.

Pregnancy:

• Not assigned an FDA category.
• Use is contraindicated during pregnancy due to insufficient human data and animal studies suggesting possible teratogenic effects.

Lactation:

• Unknown whether Almitrine or Raubasine is excreted into human milk.
• Use during breastfeeding is not recommended. If treatment is essential, breastfeeding should be discontinued.

Caution:

• Use in women planning to become pregnant should be avoided.

• Primary Class: Respiratory and Cerebral Vasodilator
• Subclasses:
• Almitrine: Respiratory stimulant and pulmonary vasoregulator
• Raubasine: Vasoactive alkaloid (alpha-adrenergic antagonist, cerebral vasodilator)

• Known hypersensitivity to Almitrine, Raubasine, or excipients
• Severe hepatic impairment
• Pregnancy and lactation
• Children and adolescents
• Hyperthyroidism
• Severe peripheral arterial obstruction with risk of tissue necrosis
• Acute stroke or unstable neurological conditions

• Peripheral Neuropathy:
  Almitrine is associated with dose- and duration-dependent peripheral neuropathy. Limit treatment to 3 months; monitor for early signs such as numbness or tingling.
• Weight Loss and Anorexia:
  Unexplained weight loss may occur. Monitor body weight during prolonged use.
• CNS Effects:
  Dizziness, insomnia, and agitation may occur; caution in elderly.
• Hepatic Monitoring:
  Periodic liver function testing is advised during treatment.
• Use in COPD:
  Almitrine should not be used as a primary therapy in respiratory insufficiency. It is not a substitute for oxygen or bronchodilator therapy.
• Avoid Alcohol Consumption:
  Alcohol may exacerbate CNS side effects.

Common Side Effects:

• Neurological: Paresthesia, dizziness, insomnia, headache
• Gastrointestinal: Nausea, abdominal pain, anorexia
• General: Weight loss, fatigue

Serious or Rare Adverse Effects:

• Peripheral neuropathy: May occur with prolonged use
• Elevated liver enzymes or hepatotoxicity
• Mood changes or irritability (in sensitive individuals)
• Hypotension (mild, reversible)

Timing & Severity:

• Neuropathy risk increases with use >3 months
• Gastrointestinal and CNS effects may occur early and are usually mild

• Alcohol: Increases risk of CNS depression and neurotoxicity
• CNS Depressants (e.g., sedatives, antihistamines): Additive drowsiness and dizziness
• Antihypertensive Agents: Potential additive hypotensive effect
• Monoamine Oxidase Inhibitors (MAOIs): Risk of exaggerated vasodilation or CNS stimulation
• Hepatic Enzyme Modulators:
• Enzyme inhibitors (e.g., ketoconazole) may increase Almitrine levels
• Enzyme inducers (e.g., rifampin) may reduce therapeutic effect

• Duration of Therapy Reminder:
  Labeling in several countries now emphasizes strict limitation to 3-month use due to neuropathy risk.
• EMA Review:
  Recent European assessments maintained current approvals but advised enhanced monitoring.
• No new safety alerts from WHO or FDA as of the latest update.

• Temperature: Store at room temperature between 15°C and 25°C
• Humidity: Keep in a dry place, away from moisture
• Light Protection: Store in original packaging to protect from light
• Precautions:
• Do not refrigerate or freeze
• Keep out of reach of children
• Do not use expired or damaged tablets