Side Effects & Interactions

Which concomitant diseases are contraindications for the use of Axura®?

The only contraindication for the use of Axura® is hypersensitivity to the active substance or to any of the excipients. However, there are a few other concomitant diseases where special precautions need to be taken. These are severe renal impairment, epilepsy, recent myocardial infarction, congestive heart failure and uncontrolled hypertension.

What medications should not be given during Axura® treatment?

Due to the pharmacological effects and the mechanism of action of memantine, the following interactions may occur:

• The mode of action suggests that the effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with NMDA-antagonists such as memantine.
• The effects of barbiturates and neuroleptics may be reduced. Concomitant administration of memantine with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dosage adjustment may be necessary.
• Concomitant use of memantine and amantadine should be avoided, owing to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA-antagonists. The same may be true for ketamine and dextromethorphan. There is one published case report on a possible risk also for the combination of memantine and phenytoin.
• Other drugs such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine that use the same renal cationic transport system as amantadine may also possibly interact with memantine, leading to a potential risk of increased plasma levels.
• There may be a possibility of reduced excretion of hydrochlorothiazide (HCT) when memantine is co-administered with HCT or any combination with HCT.
• Some factors that may raise urine pH may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivorous to a vegetarian diet, or a massive ingestion of alkalizing gastric buffers. Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria.

Is it possible to combine Axura® and medication for Parkinson's disease?

Yes it is, but a combination of memantine and amantadine should be avoided. The mode of action suggests that the effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with NMDA-antagonists such as memantine. Therefore, the dosage of the above mentioned drugs may have to be adjusted.

What side effects are to be expected during Axura® treatment?

In general, observed side effects are mild to moderate. Common side effects (frequency 2% and less!) are hallucinations, confusion, dizziness, headache and tiredness. Uncommon side effects are anxiety, hypertonia (increased muscle tone), vomiting, cystitis and increased libido.

Why are side effects less frequent under treatment with memantine than under treatment with cholinesterase inhibitors?

Memantine and cholinesterase inhibitors have different mechanisms of action. While memantine is a moderate affinity, uncompetitive NMDA receptor antagonist, cholinesterase inhibitors block an enzyme that breaks down the neurotransmitter acetycholine. Since the peripheral cholinesterase is also inhibited to a certain degree, the typical cholinergic side effects like nausea, vomiting, diarrhea and muscle cramps will result. In contrast, memantine counteracts glutamatergic overstimulation under pathophysiological conditions while physiological glutamatergic neurotransmission remains intact.

Is it safe to combine Axura® and cholinesterase inhibitors?

Yes, a combination of Axura® and cholinesterase inhibitors has been shown to be safe and well tolerated in a clinical trial(6) and a postmarketing surveillance(7).

Since starting Axura® one of my patients has become very active and restless. Should I reduce the dose?

Initial side effects are likely to disappear after having reached the 20mg/d dose. If the patient continues to be restless (which is not a common side effect), dose reduction to one tablet in the morning is recommended. Increased activity may also reflect the efficacy of Axura®.

Are there any special restrictions for patients with renal impairment?

In patients with normal to mildly impaired renal function (serum creatinine levels of up to 130 µmol/l) no dose reduction is needed. In patients with moderate renal impairment (creatinine clearance 40-60 ml/min/1.73 m2) the daily dose should be reduced to 10 mg per day. No data are available for patients with severely reduced kidney function.

Are there any special restrictions for hypertensive patients?

In most clinical trials, patients with recent myocardial infarction, congestive heart failure (NYHA III, IV), and uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely monitored.