Effect of oral pseudoephedrine on blood pressure and heart rate: a meta-analysis – Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews

SM Salerno, JL Jackson, and EP Berbano.

Review published: 2005.

CRD summary

This review of adults aged 20 to 63 years concluded that oral pseudoephedrine modestly increased systolic blood-pressure and heart rate, particularly with immediate-release formulations, higher doses of medication and short-term medication administration. The authors’ conclusions are reasonable, but the effect of pseudoephedrine may have been overestimated given the inclusion criteria used for the review.

Authors’ objectives

To assess the effect of oral pseudoephedrine on heart rate (HR) and blood-pressure (BP).

Searching

MEDLINE and EMBASE were searched from inception to 2005; the search terms were reported. The Cochrane CENTRAL Register and the Cochrane Database of Systematic Reviews were also searched, and the reference lists of reviewed articles were scrutinised for additional articles.

Study selection

Study designs of evaluations included in the review

Randomised controlled trials (RCT) were eligible for inclusion.

Specific interventions included in the review

Placebo-controlled studies where at least one group received a sympathomimetic medication were eligible for inclusion. All included trials used pseudoephedrine. Thirty-one arms used immediate-release formulations and 14 used sustained-release formulations. The doses ranged from 15 to 240 mg.

Participants included in the review

Studies of adults were eligible for inclusion. Pseudoephedrine indication varied between studies and was not consistently reported. In many studies the participants were exercising. The mean patient age was 34.9 years (range: 20 to 63). Thirty-four per cent of the participants were female.

Outcomes assessed in the review

The studies were required to report extractable outcomes; studies that reported outcomes as ‘no change’ with no supporting data were excluded. The outcomes of interest were systolic BP, diastolic BP and HR. The authors stated that they also extracted data on adverse events.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Assessment of study quality

Study quality was assessed using the Jadad scale which comprises six items: randomisation, blinding, withdrawals and drop-outs, statistical analyses, inclusion and exclusion criteria, and method of assessing adverse treatment effects. Two reviewers independently assessed study quality, and any disagreements were resolved by consensus.

Methods of synthesis

How were the studies combined?

A meta-analysis was performed using the random-effects model of DerSimonian and Laird to calculate summary WMDs.

Publication bias was assessed using the methods of Egger et al. If heterogeneity was found, its possible impact was estimated using the ‘trim-and-fill’ method of Duval and Tweedie.

How were differences between studies investigated?

Heterogeneity was assessed visually using Galbraith plots and with the Q (chi-squared) statistic using the Mantel-Haenzel test. Subgroup analyses were conducted to explore differences between the following: extended- and immediate-release preparations of each drug; short-term (less than 1 day) and long-term administration of drugs; low and high (greater than 60 mg pseudoephedrine) doses of medications; participants with and without hypertension; and studies that did not include women. Sensitivity analyses were performed for high versus low (Jadad score less than 6) study quality and for studies that specifically included baseline BP readings immediately before administration of the treatment. Individual studies were sequentially removed from the analysis to investigate the effect on the results. Several potential sources of heterogeneity (year of publication, type of medication, inclusion of multiple sexes, length of studies, study quality scores) were explored using meta-regression and stratified analyses.

The normality of the distribution of the results was explored using the Shapiro-Wilks test of normality.

Results of the review

Twenty-four RCTs, with 1,285 participants, were included in the review. Sixteen were crossover trials and 8 were parallel-group trials.

The mean Jadad score was 5.9 (standard deviation 1.7) out of a maximum possible score of 8. The scores ranged from 1 to 8. Many of the included studies pooled baseline vital sign data for the treatment and placebo groups.

Pseudoephedrine was found to cause a statistically significant increase in systolic BP (WMD 0.99 mmHg, 95% CI: 0.08, 1.90) and HR (2.83 beats/minute, 95% CI: 2.03, 3.63) compared with placebo. The increase in diastolic BP was not statistically significant (0.63 mmHg, 95% CI: -0.10, 1.35). No clinically significant adverse events were reported.

There was no evidence of publication bias for either systolic or diastolic BP, but there was for HR. With trim-and-fill, the effect was reduced to 1. 7 beats/minute (95% CI: 0.96, 2.6).

All effectiveness results were heterogeneous (P<0.001). The subgroup analyses found that while immediate-release formulations significantly elevated systolic BP, sustained release formulations had no effect. Formulation type did not alter the overall effect on diastolic BP. HR was significantly elevated with immediate- and sustained-release formulations. In participants with known, stable (treated) hypertension, the results were the same as overall, but the increase in HR was not statistically significant. There were no significant effects in participants who underwent exercise testing. However, the authors warned that these comparisons might have been underpowered.

There were no effects of age, country or year of study, study design, or duration of washout on the results. No single study overly affected the results. The treatment effects on systolic BP and HR were normally distributed. A dose-response relationship was found for all outcomes. Longer study duration was associated with less of an effect on systolic BP, but had no effect on diastolic BP or HR. Studies with more women demonstrated less effect on all three outcomes. The authors stated that separate analyses of studies with separate baseline data for the placebo and control groups and higher quality studies showed less pronounced effects on outcome, though this analysis was not reported.

Authors’ conclusions

Pseudophedrine modestly increased systolic BP and HR. These effects were greatest in magnitude with immediate-release formulations, higher doses of medication and short-term medication administration. It was not possible to reach a conclusion about the effect in older populations, owing to insufficient data.

Implications of the review for practice and research

Practice: The authors stated that the risk-benefit ratio should be evaluated carefully before using sympathomimetic agents in individual patients most at risk of BP and HR elevations. They encourage physicians to instruct patients with cardiovascular disease to monitor their BP carefully after starting therapy.

Research: The authors stated that future research should examine subsets of the population at risk of autonomic insufficiency, such as diabetic patients, to determine whether exaggerated BP responses to oral pseudoephedrine are present.

Bibliographic details

Salerno S M, Jackson J L, Berbano E P. Effect of oral pseudoephedrine on blood pressure and heart rate: a meta-analysis. Archives of Internal Medicine 2005; 165(15): 1686-1694. [PubMed: 16087815]

Original Paper URL

http://archinte.ama-assn.org

Indexing Status

Subject indexing assigned by NLM

MeSH

Blood Pressure /drug effects; Dose-Response Relationship, Drug; Ephedrine /pharmacology; Female; Heart Rate /drug effects; Humans; Male; Sex Factors; Sympathomimetics /pharmacology

AccessionNumber

12005008373

Database entry date

28/02/2006

Don’t let decongestants squeeze your heart

As many over-the-counter decongestants get a new ingredient, you might want to look for alternatives.

For nasal congestion due to colds and allergies, millions of Americans reach for an over-the-counter decongestant to clear a stuffy nose. Some read the warning label: “Do not use this product if you have heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland unless directed by a doctor.” Few heed it.

But it might be good to pay attention to the decongestant’s warning. Many of your favorite products containing a decongestant are no longer so easily available on pharmacy shelves. For example, products containing pseudoephedrine, the active ingredient in Sudafed and many other non-prescription decongestants, now are purchased “behind the counter.” You don’t need a prescription, but you do have to ask a pharmacist or clerk for them and show an ID or sign a log.

Fearing that customers will shy away from asking a pharmacist or clerk for these products, some drug companies are replacing pseudoephedrine with another over-the-counter decongestant called phenylephrine.

Is phenylephrine just like pseudoephedrine? Regarding its effectiveness as a treatment for nasal congestion, the answer is no. In fact, some research has found that at the current recommended doses of phenylephrine it offers minimal symptom improvement. It may be safer for people with high blood pressure and heart disease, but there is not enough research to be certain.

Decongestant effects beyond the nose

A stuffy nose is a hallmark of the common cold and allergic rhinitis. Chalk this symptom up to the body’s immune response.

When you have a cold, virus-infected cells in the nose, sinuses, and throat attract a flood of white blood cells. These infection fighters churn out substances that kill the cold virus but also swell nasal membranes and make the body produce extra mucus.

In allergic rhinitis, the immune cells trigger the same type of response in the nose, sinuses and throat.

Pseudoephedrine constricts blood vessels in the nose and sinuses. This shrinks swelling and drains fluids, letting you breathe easier again. Unfortunately, the drug doesn’t affect only the head — it tightens blood vessels throughout the body.

One pseudoephedrine side effect is a possible increase in blood pressure. In general, this increase is minimal in people with controlled high blood pressure. But prior studies found a small percent of people had marked increases in blood pressure. If you have high blood pressure and need to take pseudoephedrine you should have your blood pressure checked more often.

The FDA says that pseudoephedrine is safe when taken as directed. Indeed, millions of people use it each year without any dire consequences. That doesn’t mean it’s risk free. Over the years, there have been reports of heart attacks, strokes, disturbed heart rhythms, and other cardiovascular problems linked with use of pseudoephedrine.

Alternatives to decongestants

Alternatives to oral decongestants are available. In the drug realm, antihistamines such as diphenhydramine (Benadryl), chlorpheniramine (Chlor-Trimeton), cetirizine (Zyrtec), and loratadine (Claritin) can help with a stuffy nose are safe for the heart.

Nasal sprays deliver a decongestant right where you need it. In theory, this should minimize cardiovascular effects. However, nasal decongestant sprays should be used only for several days because it can lead to rebound nasal congestion.

If you want to avoid medications altogether, you can try a variety of natural decongestants to clear your head. Breathe Right nasal strips may help you breathe better at night. A steamy shower or a hot towel wrapped around the face can relieve congestion. Drinking plenty of fluids, especially hot beverages, keeps mucus moist and flowing. Some people swear by spicy foods, and we would be remiss if we did not mention chicken soup.

Photo: spukkato/iStock/Getty images Plus

Safety of drugs for the treatment of colds

Modern decongestants (drugs that reduce mucosal edema) should be considered from the standpoint of safe use in a large number of patients with acute respiratory viral infections. At present, the Pharmaceutical Committee of the Ministry of Health of the Russian Federation has transferred from the category of over-the-counter to prescription drugs containing pseudoephedrine and phenylpropanolamine, since they significantly increase the likelihood of developing such severe adverse drug reactions, as hemorrhagic stroke and subarachnoid hemorrhage. Thus, when using phenylpropanolamine in low doses, the risk of stroke is 1.23 (p<0.25), in high doses it increases 13 times. The most suitable for OTC are preparations containing phenylephrine as a decongestant, which effectively eliminates swelling of the nasal mucosa with a small number of side effects and practically does not interact with other drugs. Rigorous Implementation of the decision to ban the sale of products containing pseudoephedrine and phenylpropanolamine without a prescription will significantly improve the safety of self-treatment of patients with “cold” diseases.

The problem of the safety of drugs used for the symptomatic treatment of acute respiratory viral infections (ARVI), the so-called colds, has been actively discussed by the medical community in recent years [1, 2]. Interest in this problem is caused by several circumstances. Firstly, the number of consumers of these drugs annually amounts to tens and hundreds of millions of people. Only in the USA , according to rough estimates, every adult has ARVI 2-3 times a year, and every child – up to 6-8 times, and in 4% of cases these infections are complicated by sinusitis, acute otitis media and other bacterial infections [ 3]. Secondly, many of these drugs are complex, containing components with different mechanisms of action aimed at reducing the severity of various symptoms of the disease (fever, rhinorrhea, arthralgia, intoxication). As you know, in combined treatment, it is necessary to take into account not only the possibility of prescribing each of the components, but also the possibility of their pharmacological interaction, as well as interaction with those drugs that the patient can take simultaneously, for example, for the treatment of chronic diseases. The provided opportunities for self-treatment with these drugs and their constant (not always objective) advertising in the media create certain grounds for their uncontrolled and not always safe use [4].

Usually, such complex agents include paracetamol, which has antipyretic and analgesic effects; pseudoephedrine, phenylpropanolamine or phenylephrine can be used as decongestants. In addition, such products usually contain ascorbic acid.

The safety issues of paracetamol use have been studied in sufficient detail [5–7]. It is considered one of the safest remedies for the symptomatic treatment of fever and pain in colds and flu.

The situation with the safety of drugs that reduce swelling of the nasal mucosa and improve / restore nasal breathing is much more complicated. They differ from each other in the nature and severity of systemic effects, and therefore in the frequency of side effects, although the action on the vessels of the mucous membrane is based on the same mechanism – stimulation of a ₁ -adrenergic receptors with vasoconstriction, reduction of mucosal edema nasal cavity and reduction of rhinorrhea.

One of the first decongestants was ephedrine, the advantages of which can be considered a rapid and prolonged anti-edematous effect due to the resistance of the drug to the destructive action of enzymes. However, when using ephedrine, undesirable side effects from the central nervous system develop, as well as addiction and addiction to it, and therefore it is on list A and is not intended for widespread use.

Pseudoephedrine, a stereoisomer of ephedrine, in combination with paracetamol effectively eliminates swelling of the nasal mucosa and is used as a decongestant in otorhinolaryngology to prevent the development of bacterial sinusitis [8]. It does not stimulate the central nervous system as pronouncedly as ephedrine, but at the same time increases heart rate (HR) and blood pressure (BP) [9]. Of particular concern is the fact that pseudoephedrine significantly increases the resistance of cerebral arteries, which increases the risk of developing hemorrhagic stroke [10]. Elderly patients are most susceptible to this effect, which creates additional difficulties in prescribing the drug and requires careful medical monitoring of the treatment process. It was this circumstance that led Western countries to stop dispensing over-the-counter drugs containing pseudoephedrine a few years ago, and since November 2000 – and the Russian Federation. In addition, cases of pseudoephedrine use for non-medical purposes are known, which imposes additional responsibility on the doctor prescribing treatment.

Phenylpropanolamine has been one of the promising decongestants until recently. Its advantages can be considered the optimal speed of the onset of the effect and a sufficient duration of action. At the same time, a possible connection between the development of cerebrovascular accidents and the use of phenylpropanolamine has long been discussed in the literature [11–13]. Of particular concern was the fact that the possibility of CNS damage was not excluded not only in elderly patients or those with a history of cerebrovascular accidents, but also in young, formerly healthy patients.

In 1992, the FDA recommended that large-scale pharmacoepidemiological studies should be conducted on phenylpropanolamine, which is widely used not only as a decongestant, but also as an anorexigenic agent. Not so long ago, the results of one such prospective study called HSP (Hemorrhage Stroke Project), which was conducted in 1994-1999, were published. in the USA [14]. It included all patients admitted to study centers with a diagnosis of hemorrhagic stroke or subarachnoid hemorrhage. At the same time, the anamnesis was carefully studied for the use of phenylpropanolamine. In total, the study included 702 patients who received this drug before hospitalization, and 1376 patients with stroke who did not receive it (control group). The relative risk of developing hemorrhagic stroke as a result of the use of low-dose phenylpropanolamine for the symptomatic treatment of colds and flu was 1.23 (p<0.25), which may indicate the danger of its use. This side effect seems to be dose-dependent, which confirms the fact that the risk of cerebrovascular accident increases by 13 times (relative risk 15. 92; p<0.01) in cases where phenylpropanolamine was used in high doses to reduce appetite.

Phenylpropanolamine, like all sympathomimetics, can cause an increase in blood pressure, which in some cases can cause the development of hemorrhagic stroke when it is used [15]. In addition, when using it, there is a risk of cardiac arrhythmias, tremors, feelings of anxiety and insomnia, which is due not only to the direct action of the drug, but also to the effects of its metabolites [16].

Given the interaction of phenylpropanolamine with other drugs, the physician should prescribe it with caution to patients receiving b-adrenergic receptor blockers, MAO inhibitors, theophylline, bromocriptine [17].

Based on the results of epidemiological studies and based on the high risk of developing severe complications, the State Pharmacological Committee of the Russian Federation in November 2000 decided to limit the use of phenylpropanolamine and pseudoephedrine in the Russian Federation and transfer preparations containing these substances to the list of prescription drugs regardless of the amount of these substances in the dosage form.

An alternative to the above agents is currently phenylephrine, which is considered a safe oral decongestant in most countries [18, 19]. It is not a catecholamine, since it contains one hydroxyl in the aromatic nucleus, but otherwise reproduces the chemical structure of epinephrine. According to pharmacological properties, it belongs to selective a ₁ -adrenergic agonists, due to which it exhibits vasoconstrictor properties, due to which swelling of the nasal mucosa decreases. The bioavailability of phenylephrine after oral administration is 40%, and first-pass metabolism occurs not in the liver, but in the intestinal mucosa, which predetermines the absence of its interaction with other drugs metabolized in the liver. The drug at a dose of 10 mg causes an objectively recorded restoration of the patency of the nasal passages in patients with rhinitis (a decrease in resistance when breathing through the nose at 15–30–60 minutes by 11–21–38%, respectively) [20]. In OTC doses, phenylephrine practically does not increase blood pressure and does not have a stimulating effect on the central nervous system.

For the period 1995–2000 In the UK, more than 19 million packs of drugs for the symptomatic treatment of colds containing paracetamol, phenylephrine and ascorbic acid were sold. Only in 2 cases, information was obtained on the development of side effects that did not pose a threat to the health of patients [21].

Despite the favorable pharmacokinetic profile of phenylephrine when administered orally, it should be borne in mind that in patients with arterial hypertension it can cause an increase in blood pressure. However, as a rule, for the development of these effects, it is necessary to use the drug orally in a single dose of 40-60 mg, which is 4 times higher than the dose of phenylephrine in over-the-counter combined preparations. Despite this, it is advisable for patients with arterial hypertension and other pathologies of the cardiovascular system, hyperthyroidism, diabetes mellitus to consult with their doctor about the use of drugs containing phenylephrine.

Thus, phenylephrine remains the only safe systemic drug that is approved for OTC in the Russian Federation as part of combination products intended for the treatment of patients with colds and influenza.

It is important to unconditionally implement the decision to ban the sale without a prescription of drugs containing pseudoephedrine and phenylpropanolamine, as drugs, only a doctor can compare the benefits of using them with the possible risk of developing adverse drug reactions. In this work a big role is played by the pharmacist, who should take a more responsible approach to dispensing drugs for symptomatic treatment, seemingly banal diseases such as SARS, and inform buyers and patients about the safest of them.

In our opinion, in Russia there is a need to conduct large-scale pharmacoepidemiological studies on the safety of over-the-counter drugs widely used for colds.

E.E. Zvartau, O.I. Karpov,
Institute of Pharmacology
im. A.V. Valdman St. Petersburg State Medical University
acad. I.P. Pavlova

instructions for use, dosage, composition, analogues, side effects / Pillintrip

WARNINGS

Contained as part of PRECAUTIONS Section

PRECAUTIONS

Risks from concomitant use with benzodiazepines or other CNS depressants

opioids, including HYCOFENIX, with benzodiazepines or other CNS depressants, including alcohol, may lead to deep sedation, respiratory depression, coma and death. Because of these risks, avoid using opioid cough medicines in patients taking benzodiazepines, other CNS depressants, or alcohol.

Observations have shown that the concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related deaths compared with the sole use of opioids. Due to similar pharmacological properties, a similar risk is expected with concomitant use of opioid cough agents and benzodiazepines, other CNS depressants, or alcohol.

Advise patients and nurses about the risk of respiratory depression and sedation when using HYCOFENIX with benzodiazepines, alcohol, or other CNS depressants.

Respiratory depression

Hydrocodone bitartrate, one of the active substances in HYCOFENIX, causes dose-related respiratory depression by acting directly on the brainstem respiratory centers. Overdose of hydrocodone bitartrate has been associated with fatal respiratory depression, and use of hydrocodone bitartrate in children under 6 years of age has been associated with fatal respiratory depression. Be careful when administering HYCOFENIX as respiratory depression is possible. If respiratory depression occurs, you may be counteracted by using naloxone hydrochloride and other supportive measures if needed.

Addiction

Hydrocodone may cause morphine addiction and therefore may be abused. Psychological dependence, physical dependence and tolerance may develop with repeated administration of HYCOFENIX. Give and administer HYCOFENIX with the same care as other opioids.

Head trauma and increased cerebral pressure

The effects of opioid respiratory depression and your ability to increase CSF pressure may be greatly exaggerated by head trauma, other intracranial lesions, or an existing increase in intracranial pressure. In addition, opioids cause side effects that may mask the clinical course of head trauma patients. In these patients, HYCOFENIX should be avoided.

Activities that require mental alertness

Hydrocodone bitartrate, one of the active substances in HYCOFENIX, may cause significant drowsiness and impair mental and/or physical abilities that are necessary to perform potentially hazardous tasks such as driving or operating machinery. Advise patients to avoid hazardous tasks requiring mental alertness and motor coordination after taking HYCOFENIX. Concomitant use of HYCOFENIX with alcohol or other central nervous system depressants should be avoided as additional central nervous system impairment may occur.

Acute abdominal conditions

HYCOFENIX should be used with caution in patients with acute abdominal disease, as hydrocodone administration may obscure the diagnosis or clinical course of patients with acute abdominal disease. Concomitant use of other anticholinergics with hydrocodone may result in paralytic ileus.

Concomitant use with anticholinergics

Concomitant use of anticholinergics with hydrocodone may result in paralytic ilium. Use caution when using HYCOFENIX in patients taking anticholinergic drugs.

Concomitant use with monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants

HYCOFENIX should not be used in patients receiving MAOI therapy or within 14 days of discontinuing such therapy. The use of MAOIs or tricyclic antidepressants with hydrocodone bitartrate may enhance the effect of the antidepressant or hydrocodone.

Cardiovascular and central nervous system effects

The pseudoephedrine hydrochloride contained in HYCOFENIX may cause cardiovascular and central nervous effects such as insomnia, dizziness, weakness, tremors or arrhythmias in some patients. In addition, stimulation of the central nervous system by spasms or cardiovascular collapse with concomitant hypotension has been reported. Therefore, HYCOFENIX should be used with caution in patients with cardiovascular disease and should not be used in patients with severe hypertension or coronary artery disease.

persistent cough

HYCOFENIX should not be used in patients with persistent or chronic cough, eg. smoking, asthma, chronic bronchitis or emphysema or cough accompanied by excessive mucus (phlegm).

Dosage

Patients should be advised to measure HYCOFENIX using accurate milliliters. Patients should be informed that homemade spoon is not an accurate indicator and may lead to overdose, which can lead to serious side effects. Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and to receive instructions on how to measure the correct dose.

Co-existing conditions

HYCOFENIX should be used with caution in patients with diabetes, thyroid disease, Addison’s disease, prostatic hypertrophy or urethral stricture, and asthma.

Renal insufficiency

HYCOFENIX should be used with caution in patients with severe renal insufficiency.

Renal failure

HYCOFENIX should be used with caution in patients with severe hepatic dysfunction.

Patient Monitoring Information

Overdose

Do not advise the patient to increase the dose or frequency of dosing of HYCOFENIX as serious side effects such as respiratory depression may occur in case of overdose.

Dosage

Advise the patient to measure HYCOFENIX with an accurate millimeter measuring device. Patients should be advised that the homemade teaspoon is not an accurate measuring device and may lead to overdose, especially if measured in half a teaspoon. Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and to receive instructions on how to measure the correct dose.

Interactions with benzodiazepines and other central nervous system depressants

Inform patients and nurses that potentially fatal additive effects may occur when HYCOFENIX is used with benzodiazepines or other central nervous system depressants, including alcohol. Because of this risk, patients should avoid concomitant use of HYCOFENIX with benzodiazepines or other CNS depressants, including alcohol.

Activities that require mental alertness

Advise patients to avoid hazardous tasks that require mental alertness and motor coordination, eg. operating machinery or driving a car, as HYCOFENIX may cause significant drowsiness.

Addiction

Beware of patients who contain HYCOFENIX hydrocodone bitartrate and may cause addiction.

MAO

Patients should be informed that due to its pseudoephedrine component, you should not use HYCOFENIX with an MAOI or for 14 days after you stop using an MAOI

Non-clinical toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenicity, mutagenicity and reproduction studies have not been conducted with HYCOFENIX; however, information is published on individual active substances or related active substances.

Hydrocodone

Carcinogenicity studies have been performed with codeine, an opiate related to hydrocodone. In two-year studies in f344/N rats and B6C3F1 mice, codeine showed no signs of tumor genius at dietary doses up to 70 or more. 400 mg/kg/day (about 30 or. 80 times the MRDD of hydrocodone to mg/m ₂ – base).

Pseudoephedrine

Two-year feeding studies in rats and mice showed no evidence of carcinogenic potential with ephedrine sulfate, a structurally related drug with pharmacological properties similar to pseudoephedrine, at dietary doses up to 10 or more. 27 mg/kg (about 0.3 or. 0.5 times the MRHD of pseudoephedrine hydrochloride per mg/m ₂ base).

Guaifenesin

No carcinogenicity, genotoxicity or reproductive toxicology studies have been conducted with guaifenesin.

Use in certain populations

Pregnancy

Teratogenic effects

Pregnancy category C

There are no adequate and well controlled studies of HYCOFENIX in pregnant women. Reproductive toxicity studies have not been conducted with HYCOFENIX; however, there are studies with a single active substance or a related active substance. Hydrocodone was teratogenic in hamstern. Codeine, an opiate related to hydrocodone, increased resorption and decreased fetal weight in rats. Because animal reproduction studies do not always predict human response, HYCOFENIX should only be used during pregnancy if use justifies the potential risk to the fetus.

Hydrocodone

Hydrocodone has been shown to be teratogenic in the hamstring when administered at a dose approximately 35 times the recommended maximum human daily dose (MRHDD) (mg/m ₂ ) base with single subcutaneous dose 102 mg/kg on the day of pregnancy 8). Reproductive toxicology studies have also been conducted with codeine, an opiate related to hydrocodone. In a study in which pregnant rats were dosed during organogenesis, the dose of codeine increased the MRDD of hydrocodone by approximately 50 times (up to mg/m ₂ – base at an oral dose of 120 mg / kg / day of codeine) resorption and reduction in fetal weight; however, these effects occurred in the presence of maternal toxicity. . In studies in which rabbits and mice were dosed during organogenesis, doses of codeine resulted in approximately 25 or more. 120 times the MWGDD of hydrocodone (mg/m ₂ – basis for oral doses of 30 or.

non-teratogenic effects

crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever The intensity of the syndrome does not always correlate with duration of maternal opioid use or dose.

Work and Delivery

As with all opioids, administration of HYCOFENIX to the mother shortly before delivery may result in some respiratory depression in the neonate, especially at higher doses.

Nursing mothers

Care should be taken when administering Hycophoenix to nursing mothers. Hydrocodone and pseudoephedrine are known to be excreted in breast milk. No studies have been conducted to determine if guaifenesin is excreted in breast milk. Because many drugs are excreted in breast milk and because of possible serious side effects in nursing infants, HYCOFENIX must decide whether to stop breastfeeding or stop taking the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of HYCOFENIX in pediatric patients under 18 years of age have not been established. The use of hydrocodone in children under 6 years of age has been associated with fatal respiratory depression.

Geriatric Use

Clinical studies have not been conducted with HYCOFENIX in geriatric populations. Other reported clinical experiences with the individual active substances of HYCOFENIX found no difference in responses between the elderly and patients under 65 years of age. In general, dose selection for the elderly patient should be made with caution, usually starting at the lower end of the dose range, reflecting an increased incidence of decreased hepatic, renal, or cardiac function, as well as concomitant disease or other drug therapy. The pseudoephedrine contained in HYCOFENIX is known to be eliminated essentially via the kidney and the risk of toxic reactions to this drug may be higher in patients with renal insufficiency. Because elderly patients are more likely to have reduced renal function, care should be taken in dose selection and this may be useful in monitoring renal function.

Renal impairment

HYCOFENIX should be used with caution in patients with severe renal impairment. Pseudoephedrine is excreted largely unchanged in the urine as unchanged drug, with the rest apparently metabolized in the liver. Therefore, pseudoephedrine may accumulate in patients with renal insufficiency.

Hepatic impairment

HYCOFENIX should be used with caution in patients with severe hepatic dysfunction.