Mayapple

Scientific Name(s): Podophyllum hexandrum Royle., Podophyllum peltatum L.
Common Name(s): American podophyllum (P. peltatum), Ba jiao lian, Devil''s apple, Duck''s foot, Gwai kou, Himalayan mayapple (P. hexandrum), Hog apple, Indian podophyllum (P. hexandrum), Mandrake, Mayapple, Racoonberry, Vegetable mercury, Wild or American mandrake

Medically reviewed by Drugs.com. Last updated on May 1, 2022.

Clinical Overview

Use

Podophyllum has been used topically to treat genital warts and hairy leukoplakia. However, clinical data are lacking and toxicity of components limits use. Use as a cathartic or purgative is considered unsafe.

Dosing

Toxicity precludes home use of podophyllum, a resin derived from P. peltatum and P. hexandrum; products for oral use have been withdrawn from the market for various safety reasons. Topical preparations of podophyllum require professional application and must be rinsed off after 1 to 4 hours.

Contraindications

Use of podophyllum in pregnancy is contraindicated.

Pregnancy/Lactation

Use is contraindicated during pregnancy. Birth defects, fetal death, and stillbirth have been associated with the use of podophyllum during pregnancy. Excretion into breast milk and effects on breastfeeding infants are unknown; use during breastfeeding should be avoided.

Interactions

None well documented.

Adverse Reactions

Chronic use of mayapple as a cathartic has been associated with hypokalemia and metabolic acidosis. Topical application may cause skin irritation and chemical burns. Application to the inside of the mouth may cause transient burning, unpleasant taste, and pain.

Toxicology

Fatalities have occurred following the ingestion or topical application of podophyllum. Clinical signs appear within 12 hours and include altered mental state, tachypnea, peripheral neuropathy, nausea, hypotension, vomiting, and fever. Muscle paralysis with respiratory failure, renal failure, hallucinations, and seizures have also been reported.

Scientific Family

• Berberidaceae (bayberry)

Botany

P. peltatum, an herbaceous perennial with distribution in the United States and Canada, grows in mixed deciduous forest environments, shaded fields, shaded moist road banks, and shaded riverbanks. The plant grows to 0.3 to 0.9 m in height. Leaves are green, simple, palmate, and glabrous. The ripe fruit, which is yellow (sometimes tinged with pink, rose, or purple) with a lemon-like flavor, is collected in August or September and is the only edible part of the plant; all other parts are considered poisonous. Flowers are usually white, but some populations display pinkish, rosy, or purplish flowers. Mayapple is unique in that it bears only 2 leaves and 1 flower, which grows in the axil of the leaves. The common name refers to the May blooming of its apple blossom–like flower.(Podophyllum peltatum 2021) The rhizomes and roots are the main source of podophyllum resin, which contains podophyllotoxin, the active principle. P. hexandrum is found in Tibet, Afghanistan, Himalayan areas of Pakistan and India, Bhutan, and China. Young P. hexandrum plants only produce 1 leaf each year, while older plants produce 2 or 3 leaves each year. The rhizome occurs in irregularly cylindrical or dorsiventrally flattened, contorted, knotty pieces, yellowish-brown to earthy-brown in color and about 2 to 4 cm in length and 1 to 2 cm thick. On the upper surface is about 3 to 4 cup-shaped scars of root-scars. P. hexandrumis superior to P. peltatum in terms of its higher podophyllotoxin content in dried roots (greater than 5% compared to only 0.25% for P. peltatum).(Hameed 2014) The Latin name is derived from podos (a foot) and phyllon (a leaf), alluding to a resemblance in the palmate leaf to the webbed foot of an aquatic bird (hence the common name "duck''s foot").(Grieve 1995) A synonym of P. hexandrum is Podophyllum emodi Wall.

History

The American Indians and colonists used podophyllum resin as a cathartic and anthelmintic, an antidote for snake bite, and as a poison.(Kelly 1954) The first report in medical literature was in 1731 by Catesby in the Natural History of Carolina, Florida, and the Bahama Islands. By the mid 19th century, topical use of podophyllin to treat malignant growths was recognized. By the beginning of the 20th century, podophyllum was a common ingredient in many proprietary medicines, including Carter''s Little Liver Pills.(Conroy 1942, Schacter 1996) Anticancer activity has been associated with podophyllum resin; derivatives have been used successfully in controlled clinical trials. In 1942, a podophyllum 25% preparation formulated with mineral oil for the short-term topical treatment of condylomas demonstrated efficacy and was regarded as a therapeutic breakthrough at the time.(Longstaff 2001)

Chemistry

Podophyllum resin contains at least 16 active compounds, including podophyllotoxin, picropodophyllin, podophyllic acid, alpha- and beta-peltatins, and quercetin.(Longstaff 2001, Nantel 1997) It also contains significant quantities of the 2 flavonoids quercetin and kampherol, which comprise about 3% and 6% of the dry weight of podophyllum, respectively.(Longstaff 2001) Resin yield from the rhizomes of P. emodi is greater than from P. peltatum (approximately 12% and 3 to 6%, respectively). The podophyllotoxin structure is closely related to the aryltetralin lactone lignans that have antineoplastic and antiviral activity.(Ardalani 2017) The most studied lignan, podophyllotoxin, and its semisynthetic derivatives (etoposide, teniposide, etoposide phosphate), are of particular interest due to their cytotoxic properties. Demand for the natural podophyllotoxin needed for production of semisynthetic derivatives tends to outstrip the supply. As a result, overexploitation of Indian P. emodi Wall (P. hexandrum Royle) has resulted in listing of the species as endangered, with alternative sources being sought. Laboratory synthesis is possible, but because of the highly unusual stereochemical features of the molecule, the process is challenging and not economically viable.(Damayanthi 1998, Lamblin 2008) An aqueous extraction technique has been developed for the leaves of P. peltatum; podophyllotoxin yields of 5.2% have been achieved.(Canel 2001) Podophyllotoxin and alpha-peltatin content in the leaves is inversely proportional, indicating that the selection and cultivation of a high-yielding podophyllotoxin leaf biomass may be possible.(Moraes 2002) Cell cultures established from Podophyllum or Linum species may offer other possible sources of podophyllotoxin.(Peterson 2001)

Uses and Pharmacology

A variety of pharmacologically active lignans are present in podophyllum. These lignans (podophyllotoxin being the most well known) act as antimitotic agents.(Longstaff 2001) Similar to colchicine and vinblastine, podophyllotoxin binds to tubulin, the protein subunit of the spindle microtubules, blocking cell division in metaphase. The activity of cytochrome oxidase and succinoxidase in the mitochondria is also reduced, and DNA synthesis is blocked. This results in the slowing of cell disruption and tissue destruction.(Chang 1992, Nantel 1997) Podophyllotoxin also has an inhibitory effect on the release of iodine from the thyroid gland and catecholamine from the adrenal medulla.(Nantel 1997) A variety of pharmacologically active lignans are present in podophyllum. These lignans (podophyllotoxin being the most well known) act as antimitotic agents.(Longstaff 2001) Similar to colchicine and vinblastine, podophyllotoxin binds to tubulin, the protein subunit of the spindle microtubules, blocking cell division in metaphase. The activity of cytochrome oxidase and succinoxidase in the mitochondria is also reduced, and DNA synthesis is blocked. This results in the slowing of cell disruption and tissue destruction.(Chang 1992, Nantel 1997) Podophyllotoxin also has an inhibitory effect on the release of iodine from the thyroid gland and catecholamine from the adrenal medulla.(Nantel 1997)

Podophyllum is highly lipid soluble and is absorbed readily from the GI tract. Topical administration to large areas also can result in absorption. Little is known about the distribution of the active compounds. A podophyllic acid preparation was eliminated predominantly in the urine with a half-life of 30 minutes; podophyllotoxin is eliminated in the bile, with a half-life of 48 hours.(Cassidy 1982)

Antiviral activity

In vitro data

In vitro studies show podophyllotoxin inhibits the replication of measles, herpes simplex virus type 1, and murine cytomegalovirus.(Barnard 2004, Damayanthi 1998, Hammonds 1996)

Cancer

The severe toxicity of podophyllotoxin limits its use as a cytostatic; however, research into semisynthetic podophyllotoxin prescription pharmaceutical agents is ongoing.(Damayanthi 1998, Lamblin 2008)

In vitro data

Several components of podophyllum, including alpha- and beta-peltatins, podophyllotoxin, and its derivatives, have tumor-inhibiting properties.(Damayanthi 1998, Lamblin 2008)

Cathartic

The use of podophyllum as a laxative under any circumstances is considered unsafe by the US Food and Drug Administration (FDA)(Longstaff 2001); podophyllum has been superseded by less toxic laxatives. Podophyllum resin is a drastic cathartic. It has a marked purging action, is highly irritant to the intestinal mucosa, and produces violent peristalsis. It is suspected that these effects are caused by colonic irritation attributable to the peltatins found in mayapple.(Morton 1977)

Hairy leukoplakia

Clinical data

In a small study (N=10), a single application of a topical podophyllum 25% resin produced short-term resolution of HIV-related, hairy leukoplakia of the tongue. The reported adverse effects included burning sensation, unpleasant or altered taste, and pain. These occurred immediately after the application, were of mild to moderate intensity, and disappeared within approximately 1 hour.(Gowdey 1995)

Insecticidal activity

Experimental data

A podophyllotoxin-rich dichloromethane extract of P. hexandrum showed insecticidal activity against larvae of Drosophila melanogaster Meigen. A diet containing 2 mcmol/mL of extract killed 100% of larvae; the LC₅₀ was 0.24 mcmol/mL. Insecticidal activity of podophyllotoxins and congeners against Blattella germanica, Epilachna sparsa orientalis, and Plutella xylostella has also been reported.(Miyazawa 1999) Also a study to explore natural product–based insecticide candidates supported the potential insecticidal activity of mayapple in agriculture.(Zhang 2021)

Psoriasis

Podophyllotoxin may be a candidate for the treatment of psoriasis due to inhibition of the release of cytokines (eg, interleukin 1, tumor necrosis factor alpha); however, the mode of delivery is crucial and requires further studies.(Singh 2018)

Clinical data

A review of toxic plants used in dermatology mentions a 16-week, double-blind study in patients with stable psoriasis vulgaris (N=152), in which podophyllotoxin was applied once daily at 3 different concentrations (0.1%, 0.25%, and 0.5%). All 3 concentration induced a statistically significant improvement of selected lesions (P<0.001). A statistically significant difference from control lesions was observed after 2 weeks of treatment (P>0.001) and continued to increase during the study course.(Singh 2018)

Rheumatoid arthritis

Clinical data

CPH 82 is a semisynthetic lignan glycoside derivative of P. emodi and has been used successfully in the treatment of rheumatoid arthritis (RA), with superior efficacy to placebo as well as tolerability advantages over methotrexate demonstrated.(CPH 2003, Larsen 1989)

Double-blind studies (N=500) have demonstrated that CPH 82 is clinically more effective than placebo, sulfasalazine, azathioprine, and auranofin. CPH-82 appears to be effective in treating RA, but is not superior to methotrexate.(Singh 2018)

Warts

Topical application of podophyllum 20% to 25% resin in ethanol or benzoin tincture is a well-established, affordable, and effective remedy for genital warts.(Longstaff 2001) Lesions become blanched within a few hours of application and necrotic within 24 to 48 hours. After approximately 72 hours, the lesions begin to slough and disappear gradually without scarring.(Nantel 1997) However, continued use carries a high risk of severe adverse effects, including acute toxicity from absorption through the skin and mucous membranes, chemical burns, and painful ulceration. Therefore, preparations require professional application and must be washed off after 1 to 4 hours. The use of podophyllotoxin, the less toxic, biologically active component of podophyllum, is considered safer. Compared with crude podophyllum preparations, podophyllotoxin 0.5% is associated with superior rates of cure, lower recurrence rates, and fewer adverse effects.(Lacey 2003, Longstaff 2001) Podophyllotoxin is regarded as sufficiently safe for unsupervised application by the patient and does not need to be washed off. Although acquisition costs are higher for podophyllotoxin than for crude podophyllum preparations, a large multicenter British trial has demonstrated the economic advantages of podophyllotoxin.(Lacey 2003)

Clinical data

A review of toxic plants used in dermatology mentions a study of patients with Condyloma acuminata lesions (N=200), in which a podophyllin 25% suspension (in mineral oil) eradicated genital warts in all patients, with most lesions disappearing within 4 days after one application. In another study in women with untreated vulvoperineal warts (N=134), 71.8% of women using a podophyllotoxin 0.5% solution reported complete resolution of lesions.(Singh 2018)

In a study in patients with C. acuminata (N=60), a combination of cryotherapy followed by application of a podophyllin 25% solution was more effective than cryotherapy alone in shortening the required treatment regimen.(Sharma 2017) According to a meta-analysis of 9 randomized controlled trials, podophyllotoxin 0.5% caused complete clearance of genital warts in approximately 56% of patients. Burning sensation, pain, pruritus, and inflammation might occur at the site of application.(Maleš 2019)

Dosing

Toxicity precludes home use of podophyllum, a resin derived from P. peltatum and P. hexandrum; products for oral use have been withdrawn from the market for various safety reasons. Topical preparations of podophyllum require professional application and must be rinsed off after 1 to 4 hours.

The Centers for Disease Control and Prevention (CDC) recommends use of a 10% to 25% solution in benzoin tincture, with a maximum exposure of less than 10 cm² and a volume of 0.5 mL per treatment session for genital and perianal warts.(Workowski 2021) A meta-analysis evaluated use of podophyllotoxin 0.5% in 9 randomized controlled trials of patients with genital warts.(Maleš 2019)

Pregnancy / Lactation

While data are lacking and some study findings suggest a lack of adverse fetal outcomes with local podophyllotoxin, pregnancy is a contraindication to use of podophyllum.(Andersson 2020, Moher 1979) Podophyllum has shown teratogenicity in animals and humans. In mice, podophyllum produced a high frequency of fetal mortality following single doses of 5 to 15 mg/kg.(Longstaff 2001) Adverse effects reported during pregnancy are largely from isolated case reports and have included fetal anomalies such as limb malformations and septal heart defects. Preauricular skin tags and a simian crease were noted in an infant born to a woman treated with topical podophyllum resin from weeks 23 to 29 of pregnancy; Total contact with the drug was just 4 hours.(Karol 1980, Singh 2022) An intrauterine death has been reported in a woman treated with podophyllum for vulvar warts during week 32 of pregnancy.(Chamberlain 1972) Excretion into breast milk and effects on breastfeeding infants are unknown; use during breastfeeding should be avoided.

Interactions

None well documented.

Adverse Reactions

Chronic use of podophyllum resin as a cathartic has resulted in hypokalemia, sometimes associated with metabolic alkalosis.(Ramirez 1970) Topical application may cause skin irritation and chemical burns. Application to the inside of the mouth in the treatment of HIV-related hairy leukoplakia resulted in transient burning, unpleasant taste, and pain.(Gowdey 1995)

Toxicology

Podophyllum is caustic, with a slow and indirect action resulting from cell division arrest and impairment of other cellular processes.(Nantel 1997) Human poisoning may result from topical application or ingestion and may be acute or chronic. Rarely does poisoning result from the consumption of unripe fruit or other parts of the plant. Several cases of accidental poisoning have occurred following ingestion of Chinese herbal products adulterated with podophyllum(But 1996) or through inadvertent ingestion in place of the anticholinergic and hallucinatory plant Mandragora officinarum, also known as mandrake.(Ramirez 1970) At least 3 deaths have been attributed to podophyllum poisoning.(Balucani 1964, Ward 1954)

Neurologic manifestations are a hallmark of podophyllum toxicity. In experimental and animal studies, overexposure caused neuronal swelling, disintegration of Nissl bodies of the dorsal root ganglion neurons, and thickening of the axons.(Chang 1992) Toxic effects on the intestine, liver, pancreas, and testes were also apparent.(Chang 1992)

In an investigation of poisonings in a Hong Kong population, ingestion of podophyllum 2 to 8 g resulted in toxicity, with initial symptoms of serious vomiting and diarrhea. Neuropathy occurred 1 to 2 days later, and patients complained of numbness in the limbs and difficulty walking. Clinical findings included the absence of reflex jerks, reduced plantar responses, lack of coordination, ataxic and unsteady gait, poor standing balance, and impaired proprioception and vibration sense.(But 1996) Tachypnea, hypotension, and fever also may be present. Muscle paralysis with respiratory failure, renal failure, hallucinations, and seizures have been reported. Death generally results from cerebral, cardiovascular, renal, or hematologic complications.(Nantel 1997) Two case reports exist of neuropathy and encephalopathy following consumption of gwai-kou (derived from the roots and rhizomes of P. hexandrum) as an adulterant (high dose of podophyllin [probably greater than 20 g]); encephalopathy was present for 5 months after ingestion.(But 1996)

No specific antidote is known; emesis may be useful during the initial phases of toxicity.(McFarland 1981) Podophyllum is lipid soluble; hemodialysis is ineffective but charcoal hemoperfusion has reversed acute symptoms within hours.(Slater 1978)

Mayapple has been implicated in a generalized toxicity marked by nausea, abdominal pain, bone marrow suppression, confusion, and accompanying liver injury. The podophyllum glycosides are directly toxic to cells. However, hepatotoxicity from the plant is usually mild and greatly overshadowed by its GI, bone marrow, and neurologic toxicity.(LiverTox 2017)

Index Terms

• Podophyllum emodi Wall

References

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This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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Generic name: siponimod [ sye-POE-ni-mod ]
Drug class: Selective immunosuppressants

Medically reviewed by Judith Stewart, BPharm. Last updated on May 4, 2022.

What is Mayzent?

Mayzent is a prescription medicine used to treat relapsing multiple sclerosis (MS) in adults.

Mayzent will not cure MS, it will only decrease the frequency of relapse symptoms.

Mayzent is used only if you have a specific genotype. Your doctor will test you for this genotype.

Warnings

You should not use Mayzent if you have a serious heart condition such as "AV block," sick sinus syndrome and no pacemaker, or if you''ve recently had heart block, heart failure, a heart rhythm disorder, chest pain, heart attack, or stroke.

Mayzent can slow your heart rate when you start taking it. You will receive your first dose in a setting where your heart rhythm can be monitored. If you miss any doses, you may also need to restart Mayzent under medical observation.

You may get infections more easily, even serious or fatal infections. Call your doctor if you have a fever, chills, aches, tiredness, vomiting, confusion, neck stiffness, increased sensitivity to light, or problems with coordination, thought, vision, or muscle movement.

Before taking this medicine

You should not use Mayzent if you are allergic to siponimod, or if you have certain serious heart conditions, especially:

• "AV block" (2nd or 3rd degree);

• sick sinus syndrome (unless you have a pacemaker);

• recent (within the past 6 months) heart failure, heart attack, stroke, "mini-stroke" or TIA, chest pain (unstable angina), or other serious heart problem.

Mayzent is not approved for use by anyone younger than 18 years old.

Some heart rhythm medications can cause unwanted or dangerous effects when used with siponimod. Your doctor may change your treatment plan if you also use: amiodarone, disopyramide, dofetilide, dronedarone, flecainide, ibutilide, procainamide, propafenone, quinidine, or sotalol.

Before you take Mayzent, tell your doctor if you have never had chickenpox or if you have never received a varicella vaccine (Varivax). You may need to receive the vaccine and then wait 1 month before taking Mayzent.

To make sure Mayzent is safe for you, tell your doctor if you have ever had:

• weak immune system (caused by disease or by using certain medicine);

• an active or chronic infection;

• a very slow heart rate;

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• diabetes;

• liver disease; or

• an eye condition called uveitis.

Tell your doctor if you have recently received a vaccine, or if you are scheduled to receive a vaccine.

Siponimod may harm an unborn baby. Use effective birth control to prevent pregnancy while you are using this medicine, and for at least 10 days after your last dose. Tell your doctor if you become pregnant during this time.

If you are pregnant, your name may be listed on a pregnancy registry to track the effects of siponimod on the baby.

It may not be safe to breastfeed while using this medicine. Ask your doctor about any risk.

How should I take Mayzent?

Take Mayzent exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets.

Your doctor will check your heart function before you start taking Mayzent.

Your dose will be increased gradually during the first 5 to 6 days of taking Mayzent.

Siponimod can slow your heart rate when you start taking it. You will receive your first dose in a medical setting. Your blood pressure and heart rate may be constantly monitored for at least 6 hours after your first dose of Mayzent.

You may take Mayzent with or without food.

Siponimod affects your immune system. You may get infections more easily, even serious or fatal infections. Your doctor will need to examine you on a regular basis. Your risk of infection could last 3 to 4 weeks after you stop taking this medicine.

Always ask your doctor before you stop taking Mayzent for any reason. When you stop taking this medicine, your MS symptoms may return. In rare cases, some people who stopped taking Mayzent had MS symptoms that were worse than before or during treatment with this medicine.

If you stop taking this medicine, do not start taking it again without asking your doctor. You will need to be under medical observation when you restart this medication.

Store unopened Mayzent in the refrigerator, do not freeze.

After opening, store the medicine in the original package at room temperature away from moisture and heat.

• You may keep the blister (Starter) pack at room temperature for up to 1 week after removing the first tablet.

• You may keep the bottle of tablets at room temperature for up to 1 month after opening.

If you stop taking Mayzent, watch for signs of worsening MS, and call your doctor right away if any new or worsening symptoms appear.

Dosing information

Usual Adult Dose for Multiple Sclerosis:

CYP450 2C9 Genotype *1/*1, *1/*2, or *2/*2:
-Titration regimen: 0.25 mg orally once daily on Days 1 and 2, then 0.5 mg orally once daily on Day 3, then 0.75 mg orally once daily on Day 4, then 1.25 mg orally once daily on Day 5
-Maintenance dose: 2 mg orally once daily beginning on Day 6
NOTE: Use a starter pack for patients who will be titrated to the 2 mg maintenance dose.

CYP450 2C9 Genotype *1/*3 or *2/*3:
-Titration regimen: 0.25 mg orally once daily on Days 1 and 2, then 0.5 mg orally once daily on Day 3, then 0.75 mg orally once daily on Day 4
-Maintenance dose: 1 mg orally once daily beginning on Day 5
NOTE: Do not use the starter pack for patients who will be titrated to the 1 mg maintenance dose.
-If one titration dose is missed for more than 24 hours, therapy needs to be reinitiated with Day 1 of the titration regimen.

Comments:
-If one titration dose is missed for more than 24 hours, therapy needs to be reinitiated with Day 1 of the titration regimen.
-First-dose monitoring is recommended for patients with sinus bradycardia, first- or second-degree atrioventricular (AV) block, or a history of myocardial infarction or heart failure.
-Administer the first dose in a setting equipped to manage symptomatic bradycardia.
-Monitor patients for 6 hours after the first dose for bradycardia with hourly pulse and blood pressure measurements. Obtain an ECG in these patients at the end of Day 1.
-If any of the following abnormalities are present after 6 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves: the heart rate 6 hours post dose is less than 45 bpm; the heart rate 6 hours post dose is at the lowest value post dose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred; the ECG 6 hours post
dose shows new onset second-degree or higher AV block.
-If post dose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 6 hours post dose shows new onset second degree or higher AV block or QTc greater than or equal to 500 msec, initiate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no treatment is required. If treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.
-After the initial titration is complete, if treatment is interrupted for 4 or more consecutive daily doses, reinitiate therapy with Day 1 of the titration regimen; also complete first-dose monitoring in patients for whom it is recommended.

What happens if I miss a dose?

Call your doctor for instructions. If you miss 1 or more of your first doses, or 4 or more of your maintenance doses, you may need to take your next dose under medical observation in a medical setting.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What to avoid

Avoid getting a vaccine without first asking your doctor. While you are taking siponimod, some vaccines may not work as well and may not fully protect you from disease.

Receiving a "live" vaccine while using siponimod may cause you to develop an infection. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

If you need to receive a vaccine, you should stop taking siponimod for at least 1 week ahead of time. After receiving the vaccine, you should wait another 4 weeks before you start taking siponimod again. Do not stop taking siponimod without your doctor''s advice.

Always ask your doctor before you stop or start taking Mayzent for any reason.

Mayzent side effects

Get emergency medical help if you have signs of an allergic reaction to Mayzent: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• slow or irregular heartbeats;

• vision problems, blurred vision, eye pain, or having a blind spot or shadows in the center of your vision (vision problems may occur 1 to 4 months after you start taking Mayzent);

• headache, confusion, change in mental status;

• a seizure;

• sores in your mouth and throat, cold sores, sores on your genital or anal area;

• skin changes, unusual moles that change in color or size;

• shortness of breath;

• liver problems - nausea, vomiting, upper stomach pain, tiredness, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes).

• symptoms of meningitis - fever, chills, body aches, tiredness, nausea and vomiting, neck stiffness, increased sensitivity to light.

Common Mayzent side effects may include:

• headache;

• increased blood pressure; or

• abnormal liver function tests.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Mayzent?

Siponimod can cause a serious heart problem. Your risk may be higher if you also use certain other medicines for infections, asthma, heart problems, high blood pressure, depression, mental illness, cancer, malaria, or HIV.

Tell your doctor about all your other medicines, especially:

• drugs that weaken the immune system such as cancer medicine, steroids, and medicines to prevent organ transplant rejection; or

• other medicines to treat MS symptoms (a beta interferon, glatiramer, Avonex, Betaseron, Copaxone, Extavia, Glatopa, Rebif).

This list is not complete and many other drugs may interact with siponimod. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.

Siponimod can have long lasting effects on your body, especially on your immune system. For 3 or 4 weeks after your last dose, tell any doctor who treats you that you have used Mayzent.

Where can I get more information?

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Mayzent only for the indication prescribed.

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