Introduction to periactin (cyproheptadine)
Periactin, known generically as cyproheptadine, is a first-generation antihistamine that has been used for decades in the treatment of various allergic conditions. Unlike many modern antihistamines that are designed to be non-sedating, Periactin belongs to the older class of antihistamines that readily cross the blood-brain barrier, producing significant sedative effects alongside its antiallergic properties. Cyproheptadine is classified as a piperidine-derivative antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic activities. This multifaceted pharmacological profile makes Periactin a unique and versatile medication that extends beyond simple allergy relief. The drug acts as a potent antagonist at histamine H1 receptors, serotonin 5-HT2 receptors, and muscarinic cholinergic receptors, which explains both its therapeutic benefits and its side effect profile. Despite the advent of newer, less sedating antihistamines, Periactin remains a valuable therapeutic option for specific clinical scenarios, including conditions where its appetite-stimulating and antimigraine properties can be leveraged. For patients seeking reliable access to this medication, Happy Family Store offers a convenient source for purchasing Periactin over the counter.
Mechanism of action
The therapeutic effects of cyproheptadine arise from its complex interactions with multiple neurotransmitter receptors. At the core of its antihistamine activity is its role as a competitive antagonist of histamine at the H1 receptor site. Histamine is a biogenic amine that is important in allergic inflammatory responses. When allergens trigger mast cell degranulation, histamine is released and binds to H1 receptors on endothelial cells, smooth muscle cells, and nerve endings. This binding leads to increased vascular permeability, vasodilation, bronchoconstriction, and stimulation of sensory nerve endings resulting in itching and pain. By occupying the H1 receptor without activating it, Periactin effectively blocks these histamine-mediated effects, alleviating symptoms such as sneezing, rhinorrhea, nasal congestion, conjunctival itching, and urticaria.
Beyond its antihistamine effects, cyproheptadine exhibits significant antiserotonergic activity through antagonism at 5-HT2A and 5-HT2C receptors. The 5-HT2A receptor subtype is involved in platelet aggregation, smooth muscle contraction, and central nervous system effects including modulation of dopamine release. The 5-HT2C receptor is implicated in appetite regulation, mood, and anxiety. The blockade of these serotonin receptors accounts for several of Periactin’s unique clinical applications. The antagonism at 5-HT2C receptors in the hypothalamus is believed to reduce the satiety signaling that normally follows food intake, leading to increased appetite and weight gain. This effect is sufficiently reliable that cyproheptadine is sometimes used as an appetite stimulant in underweight patients, including children with failure to thrive, patients with cancer cachexia, and individuals with eating disorders.
The drug also possesses moderate anticholinergic activity through muscarinic receptor blockade. This property contributes to the reduction of secretory responses, particularly in the respiratory tract and salivary glands, and gives rise to typical anticholinergic side effects such as dry mouth, blurred vision, urinary retention, and constipation. Also, cyproheptadine has been shown to have calcium channel blocking properties and may inhibit the release of certain inflammatory mediators from mast cells. The drug’s ability to stabilize serotonin-mediated vasoconstriction in cranial blood vessels has led to its use in migraine prophylaxis, particularly in children who cannot tolerate other preventive medications.
The pharmacokinetic profile of Periactin supports its clinical utility. After oral administration, cyproheptadine is well absorbed from the gastrointestinal tract, with peak plasma concentrations reached within one to three hours. The drug undergoes extensive first-pass metabolism in the liver, primarily through hydroxylation and conjugation pathways mediated by cytochrome P450 enzymes. The elimination half-life ranges from approximately six to nine hours in adults, necessitating multiple daily doses for sustained therapeutic effect. Cyproheptadine is highly protein-bound and has a large volume of distribution, reflecting its extensive tissue penetration including passage across the blood-brain barrier.
Therapeutic indications and uses
Allergic rhinitis and conjunctivitis
The primary indication for Periactin is the symptomatic treatment of seasonal and perennial allergic rhinitis. Patients suffering from hay fever or dust mite allergies experience significant improvement in nasal symptoms such as sneezing, rhinorrhea, and nasal itching when treated with cyproheptadine. The drug also alleviates allergic conjunctivitis symptoms including ocular itching, tearing, and redness. However, due to its sedative properties, Periactin is generally considered a second-line option for allergies when nonsedating antihistamines such as loratadine or cetirizine are ineffective or not tolerated.
Urticaria and angioedema
Chronic idiopathic urticaria, characterized by recurrent hives lasting more than six weeks without an identifiable cause, is another well-established indication for Periactin. The drug’s strong H1 receptor antagonism effectively suppresses the wheal-and-flare response that defines urticaria. In cases of physical urticarias such as cold urticaria, solar urticaria, and cholinergic urticaria, cyproheptadine has demonstrated particular efficacy due to its additional antiserotonergic properties, which may address pathogenic mechanisms beyond histamine release. Patients with angioedema, a deeper swelling of the dermis and subcutaneous tissues, may also benefit from treatment.
Migraine prophylaxis
In pediatric populations, cyproheptadine is widely used as a first-line agent for migraine prevention. The antiserotonergic properties of the drug are believed to be responsible for its prophylactic effect against migraines. Serotonin plays a complex role in migraine pathophysiology, with both low and high serotonin states being implicated in the initiation and propagation of migraine attacks. By modulating serotonergic signaling, cyproheptadine may help stabilize cranial vascular reactivity and reduce the frequency and severity of migraine episodes. Several clinical studies have reported significant reductions in migraine frequency in children and adolescents treated with cyproheptadine, with favorable safety profiles compared to other prophylactic medications such as beta-blockers or tricyclic antidepressants.
Appetite stimulation and weight gain
The appetite-enhancing effect of cyproheptadine is one of its most distinctive clinical applications. The drug’s antagonism of 5-HT2C receptors in the hypothalamus disinhibits feeding behavior, leading to increased caloric intake and subsequent weight gain. This effect is particularly valuable in clinical situations where weight loss poses a health risk. Children with failure to thrive, patients with cystic fibrosis, individuals with cancer-related cachexia, and patients with tuberculosis or HIV-associated wasting have all been treated with cyproheptadine as an appetite stimulant. The weight gain associated with cyproheptadine use is generally modest but clinically meaningful, with studies reporting average weight increases of one to three kilograms over treatment periods of several weeks to months.
Serotonin syndrome
In the management of serotonin syndrome, a potentially life-threatening condition caused by excessive serotonergic activity, cyproheptadine is a specific antidote. The drug’s potent 5-HT2A receptor antagonism directly counters the excessive serotonin signaling that underlies the syndrome. While supportive care including benzodiazepines, cooling measures, and withdrawal of serotonergic medications remains the foundation of management, cyproheptadine can be administered orally or via nasogastric tube in moderate to severe cases to accelerate clinical improvement. Typical dosing involves a loading dose of 12 mg followed by 2 mg every two hours until clinical response is achieved.
Carcinoid syndrome
Patients with carcinoid tumors, which secrete excessive amounts of serotonin and other vasoactive substances, may experience symptoms such as flushing, diarrhea, and bronchospasm. Cyproheptadine’s antiserotonergic properties make it a useful adjunctive treatment in managing these symptoms, particularly diarrhea associated with carcinoid syndrome.
Other indications
Cyproheptadine has been investigated in several other conditions with varying degrees of evidence. In schizophrenia, some studies have suggested that adjunctive cyproheptadine may reduce negative symptoms and attenuate antipsychotic-induced extrapyramidal side effects, although the evidence base remains limited. In Cushing’s disease, cyproheptadine has been used historically to suppress ACTH secretion through its serotonergic blockade, though more definitive treatments are now preferred. The drug has also been used in the treatment of cyclic vomiting syndrome, post-traumatic stress disorder-associated nightmares, and certain dermatological conditions including lichen planus and erythema multiforme.
Dosage and administration
Adult dosing
The standard adult dosage of Periactin for allergic conditions is 4 mg administered three times daily. Some patients may require up to 32 mg daily in divided doses for optimal symptom control, particularly in severe urticaria. For appetite stimulation, typical doses range from 4 mg three to four times daily. When used as a migraine prophylactic in adults, doses of 4 mg two to three times daily are commonly employed, with gradual dose escalation to minimize sedation. For the treatment of serotonin syndrome, a loading dose of 12 mg is followed by 2 mg every two hours as needed, up to a maximum of 32 mg in a 24-hour period.
Pediatric dosing
In children, dosing is adjusted based on age and weight. For children aged two to six years, the typical dose is 2 mg two to three times daily, with a maximum daily dose of 12 mg. Children aged seven to fourteen years may receive 4 mg two to three times daily, with a maximum of 16 mg per day. For migraine prophylaxis in children, doses starting at 2 mg at bedtime are gradually increased based on response and tolerability, with most children responding to doses of 4 to 8 mg daily. As an appetite stimulant in pediatric populations, doses of 2 to 4 mg three to four times daily for patients weighing at least 10 kilograms are common.
Geriatric considerations
Elderly patients are particularly susceptible to the anticholinergic effects of cyproheptadine, including confusion, urinary retention, constipation, and falls. Older adults may also experience exaggerated sedation and cognitive impairment. Therefore, lower initial doses and careful dose titration are recommended in geriatric populations. In many cases, alternative non-sedating antihistamines are preferred for elderly patients requiring allergy treatment.
Administration instructions
Periactin tablets should be administered orally with or without food. The medication is available in 4 mg tablets in most formulations. Patients should be advised to take the medication exactly as prescribed and not to exceed the recommended dosage. The sedative effects of cyproheptadine are most pronounced during the first few days of treatment and may diminish with continued use as tolerance develops. Taking the medication at bedtime can help patients accommodate the sedative effects while maintaining daytime alertness. When used for conditions requiring continuous therapy such as chronic urticaria or migraine prophylaxis, Periactin should be taken regularly rather than on an as-needed basis to achieve optimal therapeutic outcomes.
Side effects and adverse reactions
Common side effects
The most frequently reported adverse effect of Periactin is sedation, affecting a significant proportion of patients, particularly at the onset of therapy. The degree of sedation varies among individuals and may range from mild drowsiness to deep sleepiness that interferes with daily activities. Tolerance to the sedative effect typically develops within several days to weeks of continued use. Anticholinergic effects including dry mouth, blurred vision, constipation, and urinary hesitancy are also commonly reported and result from muscarinic receptor blockade. Increased appetite and weight gain are considered therapeutic effects in some contexts but may be undesirable for patients using Periactin for allergic conditions.
Less common side effects
Gastrointestinal disturbances such as nausea, vomiting, epigastric distress, and diarrhea may occur in some patients. Neurological effects including dizziness, ataxia, incoordination, and tinnitus have been reported. Some patients experience paradoxical stimulation rather than sedation, particularly in pediatric populations, manifesting as restlessness, irritability, insomnia, and hyperactivity. Cardiovascular effects are uncommon but may include palpitations, tachycardia, and hypotension, particularly at higher doses or in patients with pre-existing cardiac conditions.
Serious adverse reactions
While serious adverse reactions to cyproheptadine are rare, they require prompt medical attention when they occur. Allergic reactions including anaphylaxis, angioedema, and severe dermatological reactions such as Stevens-Johnson syndrome have been reported rarely. Hematological abnormalities including hemolytic anemia, leukopenia, agranulocytosis, and thrombocytopenia have occurred in isolated cases. Hepatotoxicity is extremely rare but has been documented. In patients predisposed to seizures, cyproheptadine may lower the seizure threshold. Anticholinergic toxicity at very high doses can manifest as agitation, confusion, hallucinations, hyperthermia, and cardiovascular instability.
Long-term effects
Extended use of cyproheptadine raises concerns primarily related to weight gain and metabolic effects. Significant weight gain over prolonged treatment periods may contribute to obesity, insulin resistance, and metabolic syndrome, particularly in patients already at risk. The anticholinergic effects of long-term use have been associated with an increased risk of cognitive decline in elderly populations. Tachyphylaxis, or the development of tolerance to the therapeutic effects, may occur with prolonged use, requiring dose adjustments or drug holidays to maintain efficacy.
Side effect management
Management of Periactin side effects begins with appropriate dosing strategies. Starting at a low dose and gradually titrating upward can minimize initial sedation. Taking the entire daily dose at bedtime may help patients tolerate the sedative effects. Hydration and the use of sugar-free candies or gum can alleviate dry mouth. Increasing dietary fiber intake and ensuring adequate fluid consumption can help prevent constipation. If side effects persist or become intolerable, dose reduction or switching to an alternative medication may be necessary.
Contraindications and precautions
Absolute contraindications
Periactin is contraindicated in patients with known hypersensitivity to cyproheptadine or any of the excipients in the formulation. The drug should not be used in newborn or premature infants due to an increased risk of severe anticholinergic effects and central nervous system depression. Patients with narrow-angle glaucoma should avoid cyproheptadine because its anticholinergic effects can increase intraocular pressure. Similarly, patients with symptomatic prostatic hypertrophy, bladder neck obstruction, or other urinary retention conditions should not use the drug. It is also contraindicated in patients with pyloroduodenal obstruction, stenosing peptic ulcer disease, and during acute asthmatic attacks. Patients who are currently taking or have recently taken monoamine oxidase inhibitors (MAOIs) within the past two weeks should not use cyproheptadine due to the risk of prolonged and intensified anticholinergic effects.
Relative contraindications and precautions
Caution is warranted when prescribing Periactin to patients with certain medical conditions. In patients with cardiovascular disease including hypertension, ischemic heart disease, and arrhythmias, the anticholinergic effects of cyproheptadine may cause tachycardia and worsen cardiac function. Patients with hyperthyroidism may experience exaggerated cardiovascular responses. The drug should be used cautiously in patients with hepatic impairment, as cyproheptadine undergoes extensive hepatic metabolism, and accumulation may occur. Patients with renal insufficiency may require dose adjustments, although the drug’s elimination is not primarily renal. In patients with a history of seizures, cyproheptadine may lower the seizure threshold and should be used with caution. The drug may exacerbate respiratory depression in patients with chronic obstructive pulmonary disease or sleep apnea. Patients with phenylketonuria should note that some formulations of Periactin may contain phenylalanine.
Pregnancy and lactation
The safety of cyproheptadine during pregnancy has not been definitively established. The drug is classified as Pregnancy Category B in older classification systems, indicating that animal reproduction studies have not shown a risk to the fetus but adequate human studies are lacking. Cyproheptadine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The drug is excreted in breast milk and may cause sedation, irritability, or other effects in nursing infants. Nursing mothers should either avoid using cyproheptadine or discontinue breastfeeding while taking the medication.
Drug interactions
Pharmacodynamic interactions
The central nervous system depressant effects of cyproheptadine are additive with other CNS depressants including alcohol, benzodiazepines, barbiturates, opioid analgesics, sedative-hypnotics, antipsychotics, and other antihistamines. Patients should be advised to avoid or limit alcohol consumption while taking Periactin and to use caution when combining the drug with any medication that causes sedation. The anticholinergic effects of cyproheptadine are additive with other anticholinergic medications including tricyclic antidepressants, antispasmodics, antidiarrheals such as diphenoxylate and loperamide, and certain antipsychotics. Concomitant use may result in excessive anticholinergic effects including severe constipation, urinary retention, blurred vision, and cognitive impairment.
Pharmacokinetic interactions
Cyproheptadine is metabolized primarily by the cytochrome P450 enzyme system, including CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole, itraconazole, erythromycin, clarithromycin, and grapefruit juice may increase cyproheptadine concentrations and potentiate its effects and side effects. Conversely, drugs that induce CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. John’s wort may decrease cyproheptadine levels and reduce its efficacy. Monoamine oxidase inhibitors prolong and intensify the anticholinergic and CNS depressant effects of cyproheptadine and are contraindicated for concurrent use.
Specific drug interactions
The combination of cyproheptadine with serotonin reuptake inhibitors such as SSRIs and SNRIs may theoretically reduce the antidepressant efficacy of these medications through opposing serotonergic mechanisms. In clinical practice, this interaction is rarely significant at standard doses, but caution is warranted. Cyproheptadine can antagonize the effects of serotonin agonists used in migraine treatment, such as triptans, potentially reducing their efficacy. The drug may also interfere with the antihypertensive effects of guanethidine and related medications. When used concomitantly with ototoxic medications such as aminoglycoside antibiotics or high-dose salicylates, cyproheptadine may mask early signs of ototoxicity such as tinnitus and dizziness.
Special populations
Pediatric use
Periactin has been used safely in children over two years of age for appropriate indications. The potential for paradoxical CNS stimulation in children requires careful monitoring during the initial treatment period. Parents and caregivers should be advised to observe for signs of restlessness, irritability, or insomnia, which may necessitate dose adjustment or discontinuation. The appetite-stimulating effect of cyproheptadine is often intentionally utilized in underweight children, but weight gain should be monitored to ensure it remains appropriate for the child’s age and growth parameters. For migraine prophylaxis in children, cyproheptadine is considered a first-line option due to its favorable safety profile compared to other agents.
Geriatric use
Elderly patients are at increased risk for all of the adverse effects of cyproheptadine, particularly sedation, dizziness, confusion, hypotension, and anticholinergic effects. The risk of falls and fractures is increased in elderly patients taking first-generation antihistamines. Cognitive impairment, including worsening of dementia symptoms, may occur with anticholinergic medications. For these reasons, Periactin should generally be avoided in elderly patients when alternative treatments are available. When use is necessary, the lowest effective dose should be employed, and patients should be monitored closely for adverse effects.
Hepatic and renal impairment
Patients with significant hepatic impairment may experience reduced clearance of cyproheptadine, leading to higher plasma concentrations and increased risk of adverse effects. Dose reduction may be necessary, and patients with severe liver disease should be monitored closely. While renal excretion is not the primary route of elimination for cyproheptadine and its metabolites, patients with severe renal impairment may still experience accumulation of active metabolites, warranting caution in this population.
Clinical pharmacology in depth
Cyproheptadine is a dibenzocycloheptene derivative with structural similarities to tricyclic antidepressants and phenothiazine antipsychotics. The drug’s molecular formula is C21H21N and its molecular weight is 287.4 g/mol. The compound exists as a racemic mixture, and both enantiomers contribute to its pharmacological activity. The drug exhibits high affinity for H1 histamine receptors with a Ki value in the nanomolar range, indicating potent antagonism at clinically relevant concentrations. Its affinity for 5-HT2 receptors is similarly high, while its affinity for muscarinic receptors is moderate compared to other first-generation antihistamines.
Following oral administration, cyproheptadine undergoes extensive hepatic metabolism via multiple pathways. The major metabolic routes include aromatic hydroxylation, N-demethylation, and heterocyclic ring oxidation. The resulting metabolites are primarily excreted in the urine as glucuronide and sulfate conjugates, with a smaller proportion eliminated in the feces. The metabolic profile is mediated by several cytochrome P450 isoforms, with CYP3A4 playing a predominant role. This explains the potential for drug interactions with CYP3A4 inducers and inhibitors.
The onset of action for Periactin following oral administration is approximately 30 to 60 minutes, with peak effects occurring within one to three hours. The duration of action for the antihistamine effects ranges from four to six hours for most patients, although some individuals experience prolonged effects lasting up to eight hours. The drug’s half-life is approximately eight hours in healthy adults but may be prolonged in patients with hepatic impairment or in elderly individuals. Steady-state concentrations are achieved within approximately two to three days of regular dosing.
Comparison with other antihistamines
When compared to second-generation antihistamines such as loratadine, cetirizine, fexofenadine, and levocetirizine, Periactin is more sedating due to its greater lipophilicity and ability to cross the blood-brain barrier. Modern nonsedating antihistamines are actively transported out of the central nervous system by P-glycoprotein efflux pumps, limiting their CNS penetration. However, the additional pharmacological properties of cyproheptadine, particularly its antiserotonergic effects, provide therapeutic advantages in specific clinical situations that are not shared by other antihistamines.
Compared to other first-generation antihistamines such as diphenhydramine, chlorpheniramine, hydroxyzine, and promethazine, cyproheptadine has a distinct profile. While all first-generation antihistamines share the propensity for sedation and anticholinergic effects, cyproheptadine distinguishes itself through its antiserotonergic activity. This property underlies its unique applications in migraine prophylaxis, appetite stimulation, and serotonin syndrome management that are not possessed by other first-generation antihistamines. The drug also has a lower incidence of extrapyramidal side effects compared to phenothiazine-type antihistamines such as promethazine.
Patient education and counseling
Patients prescribed Periactin should receive comprehensive education about their medication. They should be advised that the drug may cause significant drowsiness, particularly during the first few days of treatment, and that they should not drive, operate heavy machinery, or engage in activities requiring mental alertness until they know how the medication affects them. Alcohol and other CNS depressants should be avoided while taking cyproheptadine. Patients should be informed about the potential for dry mouth, constipation, and other anticholinergic effects and advised on management strategies.
Patients using Periactin for allergic conditions should understand that the medication provides symptomatic relief but does not cure the underlying allergy. Those using the drug as an appetite stimulant should be counseled about dietary strategies to maximize nutritional intake. Patients should be advised not to increase the dose or frequency of administration beyond prescribed amounts, as doing so increases the risk of adverse effects without proportional therapeutic benefit. If a dose is missed, patients should take it as soon as remembered unless it is close to the time for the next scheduled dose, in which case the missed dose should be skipped and the regular schedule resumed. Doubling doses to compensate for missed doses is not recommended.
Frequently asked questions
Can periactin be used long-term?
Periactin can be used for extended periods under medical supervision for conditions such as chronic urticaria or migraine prophylaxis. However, long-term use requires periodic reassessment of the continued need for therapy and monitoring for adverse effects including weight gain, metabolic changes, and cognitive effects. Some patients develop tolerance to the therapeutic effects over time and may require dose adjustments or alternative treatments.
Is periactin safe for children?
Periactin is approved for use in children over two years of age for appropriate indications. In pediatric practice, it is commonly used for allergic conditions, migraine prophylaxis, and as an appetite stimulant. Doses are adjusted based on age and weight. Parents should monitor children for paradoxical CNS stimulation characterized by restlessness and insomnia, which can occur in some pediatric patients.
Does periactin cause weight gain?
Weight gain is a well-established effect of cyproheptadine, resulting from its blockade of serotonin 5-HT2C receptors in the hypothalamus, which reduces satiety signals and increases appetite. This effect is intentionally utilized in patients who need to gain weight but may be undesirable for others. The extent of weight gain varies among individuals and depends on dosage, duration of treatment, and dietary habits.
Can periactin be used for migraines?
Yes, cyproheptadine is used as a preventive medication for migraines, particularly in children and adolescents. It is not effective for treating acute migraine attacks but can reduce the frequency and severity of migraines when taken regularly. The antiserotonergic properties of the drug are believed to contribute to its prophylactic efficacy. Adults may also use Periactin for migraine prevention, though other agents are typically preferred as first-line options.
How does periactin compare to other allergy medications?
Periactin is more effective than many newer antihistamines at controlling certain allergic symptoms due to its additional antiserotonergic effects, but it also causes more sedation and anticholinergic side effects. For most people with simple allergic rhinitis, nonsedating antihistamines are preferred. Periactin is generally reserved for cases where sedation is desired, such as nighttime allergy relief, or for conditions such as chronic urticaria where its broader mechanism of action provides additional benefit.
Can i take periactin with other medications?
Cyproheptadine can interact with many other medications. It should not be taken with monoamine oxidase inhibitors or within two weeks of stopping them. Caution is needed when combining with other CNS depressants, anticholinergic medications, and serotonergic drugs. Patients should always inform their healthcare provider about all medications they are taking, including prescription drugs, over-the-counter medications, and herbal supplements, before starting Periactin.
What should i do if i miss a dose?
If a dose of Periactin is missed, it should be taken as soon as remembered. However, if it is almost time for the next scheduled dose, the missed dose should be skipped and the regular dosing schedule resumed. Patients should not take a double dose to make up for a missed dose. Consistent adherence to the dosing schedule is important for conditions requiring continuous therapeutic effect such as chronic urticaria or migraine prophylaxis.
Is periactin addictive?
Cyproheptadine does not have significant abuse potential and is not classified as a controlled substance. However, psychological dependence may develop in some individuals who rely on its sedative effects for sleep. Physical dependence is not typical, and discontinuation does not usually produce withdrawal symptoms, although the underlying condition being treated may recur after cessation of therapy.
Storage and handling
Periactin tablets should be stored at room temperature between 20 and 25 degrees Celsius, away from light, moisture, and heat. The medication should be kept in its original container with the lid tightly closed. All medications should be stored out of reach of children and pets. Expired or unused medication should be disposed of properly according to local regulations or through pharmacy take-back programs. Patients should not flush medications down the toilet or pour them down the drain unless specifically instructed to do so.