Melatonin (melatonin/pyridoxine HCl (vit B6))

Although pyridoxine was previously considered nontoxic even at high dosages, current evidence indicates that chronic administration of large dosages (e.g., 2 g daily) for the management of various conditions can cause severe adverse neurologic effects, and the risk to benefit of such dosages must be carefully weighed. (See Chronic Toxicity.)

Pyridoxine hydrochloride is usually administered orally; however, the drug may be given by IM, IV, or subcutaneous injection when oral administration is not feasible. In infants with seizures, pyridoxine hydrochloride should be administered by IM or IV injection.

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Pyridoxine hydrochloride reverses the therapeutic effects of levodopa by accelerating peripheral metabolism of levodopa. Concomitant administration of carbidopa with levodopa prevents the reversal by pyridoxine of levodopa's effects. Pyridoxine hydrochloride should not be administered in dosages greater than 5 mg daily to patients receiving levodopa alone.

In one study, 200 mg of pyridoxine hydrochloride daily for 1 month resulted in a 50% decrease in serum concentrations of phenobarbital and phenytoin.

Although isoniazid interferes with pyridoxine metabolism, the American Academy of Pediatrics (AAP) states that children receiving isoniazid do not need pyridoxine supplements unless they have or are likely to have nutritional deficiencies. The AAP currently recommends that children and adolescents receiving meat- and milk-deficient diets, those with nutritional deficiencies (including symptomatic children with human immunodeficiency virus (HIV) infection), infants who are breast-feeding and their mothers, and pregnant women receive pyridoxine supplements.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Melatonin/Strong Cyp1a2 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may significantly increase the area-under-curve (AUC) of melatonin by inhibiting CYP1A2.(1,2) Fluvoxamine, a strong CYP1A2 inhibitor, has also been shown to increase endogenous melatonin levels.

CLINICAL EFFECTS: The concurrent administration of melatonin and strong CYP1A2 inhibitors may result in significantly increased melatonin levels and subsequent side effects.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of melatonin recommends against the concurrent use of melatonin and CYP1A2 inhibitors.(1) The Australian manufacturer of melatonin states concurrent use of melatonin and CYP1A2 inhibitors should be avoided.(2) Patients should be monitored for increased effects of melatonin when melatonin and CYP1A2 inhibitors are used concurrently.

DISCUSSION: In a study, fluvoxamine increased the area-under-curve (AUC) and concentration maximum (Cmax) of melatonin by 17-fold and 12-fold, respectively.(2) In a case report, a 51 year old female with chronic primary insomnia who received 5 mg melatonin at bedtime and 75 mg fluvoxamine in the afternoon experienced increased nocturnal sleep, from 2.5 hours (drug free) to 4.2 hours (melatonin alone) up to 5.5 hours per night (melatonin with fluvoxamine). Both melatonin and fluvoxamine alone increased melatonin levels; however administration of melatonin alone increased melatonin levels more than fluvoxamine alone. Concurrent use of melatonin and fluvoxamine increased melatonin levels 20-fold when compared to the administration of melatonin alone.(3) In a study involving five males, 5 mg of melatonin daily was given for one week, then 50 mg of fluvoxamine was added (administered three hours apart. The AUC of melatonin increased at least nine-fold (p<0.05). The Cmax increased at least six-fold in melatonin (p<0.01), versus the Cmax in patients who received melatonin alone.(4) Strong CYP1A2 inhibitors include: enasidenib, fluvoxamine, and viloxazine.(5)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Pyridoxine/Levodopa

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Pyridoxine increases levodopa metabolism, decreasing the amount of levodopa available to the central nervous system.

CLINICAL EFFECTS: The pharmacologic effects of levodopa may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid pyridoxine in patients receiving levodopa alone; however, the interaction can be minimized by giving levodopa with a peripheral decarboxylase inhibitor (e.g. carbidopa, benserazide). Treatment with combination carbidopa-levodopa may contribute to reduced vitamin B6 levels. Higher doses of carbidopa-levodopa may increase the risk of vitamin B6 deficiency. Seizures associated with vitamin B6 deficiency have been reported in the postmarketing setting. In patients taking combination therapy with carbidopa/levodopa, evaluate vitamin B6 levels periodically while on treatment or if symptoms associated with vitamin B6 deficiency are identified. Supplement with vitamin B6 as necessary.

DISCUSSION: In patients with Parkinson's disease, as little as 10 mg of pyridoxine may reverse the clinical benefits as well as the adverse effects of levodopa. Coadministration of levodopa with either carbidopa or benserazide has minimized the effects of this interaction.

There is no enhanced messaging for this drug.

There are no contraindication contraindications for this drug.

• Autoimmune disease
• Systemic lupus erythematosus

There are no moderate contraindications for this drug.

There is no enhanced messaging for this drug.

There are no severe adverse reactions for this drug.

More Frequent

• Dizziness
• Headache disorder
• Sedation hangover effect

Less Frequent

• Abdominal pain with cramps
• Acute cognitive impairment
• CNS depression
• Concentration difficulty
• Depression
• Hypotension
• Irritability
• Nausea
• Symptoms of anxiety
• Tremor
• Vomiting

Rare or Very Rare

• Panic disorder

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