U. S. Food and Drug Administration

The Food and Drug Administration has issued warning letters to four companies selling honey-based supplements that claim to provide sexual enhancement.

Petition to Require a Black Box Warning for Erectile Dysfunction Drugs Sildenafil (Viagra), Tadalafil (Cialis) and Vardenafil (Levitra)

Public Citizen, representing more than 135,000 consumers nationwide, hereby petitions the Food and Drug Administration (FDA) pursuant to the Federal Food, Drug and Cosmetic Act 21 U.S.C. Section 355(e)(3), and 21 C.F.R. 10.30, to immediately add a black box warning regarding the risks of drug-induced blindness for the three phosphodiesterase 5 (PDE5) inhibitors that are prescribed for the treatment of erectile dysfunction [Viagra (sildenafil; Pfizer), Cialis (tadalafil; Lilly), and Levitra (vardenafil; Bayer)]. The label for Revatio, a version of sildenafil indicated for pulmonary arterial hypertension, should also be included in the changes recommended in this petition.

Public Citizen’s concern is based, in part, on our findings that 1) Viagra accounts for nineteen percent of the total cases of ischemic optic neuropathy (loss of vision) in the FDA’s adverse event database, more than 2-fold higher than that for the next most frequently-cited drug; and that 2) the number of cases of ischemic optic neuropathy per million prescriptions is 18-fold higher for patients taking Viagra compared with patients taking Lipitor, another drug used by people with similar risk factors.

Additional Requests

This petition also strongly urges the FDA to require that a “Dear Doctor” letter be sent to all physicians informing them about the signs and symptoms of non-arteritic ischemic optic neuropathy (NAION), an often irreversible loss of vision. Men who have had a previous attack of NAION in one eye should not take these drugs since these men are at increased risk of NAION in the other eye, especially if they have other risk factors such as diabetes and hypertension.

In order to inform patients, FDA should require the mandatory distribution by pharmacists of scientifically accurate information for consumers, written in non-technical language in the form of FDA-approved Medication Guides, with each new and refill prescription for these drugs. The current patient information leaflets (not FDA-approved) are given to patients when a prescription is filled and several patient information leaflets that we have collected do not adequately warn about this serious adverse reaction.

Finally, in order to try and define the causes and prevalence of NAION due to these drugs, FDA should require the manufacturers to establish a registry of all patients diagnosed with NAION and to immediately inform the FDA of new cases.

Background

NAION is a pathologic condition triggered by blockage of blood flow to the eye that is sudden but painless in onset and frequently leads to permanent blindness, usually in one eye. The exact causes are unknown, but it often appears upon first awakening and thus has been hypothesized to be precipitated by hypotension occurring during sleep, mainly in people over the age of 50.

NAION first came to public attention on May 27, 2005, when the FDA announced that it was in discussions with Pfizer to update its Viagra label to mention loss of vision. The FDA announcement was apparently triggered by an article published in the March 2005 issue of the Journal of Neuro-Ophthalmology that described seven new cases of NAION apparently linked to the use of Viagra.[1] Although this article produced the first major public focus on the relation of Viagra to this disease, there have been 19 cases in the medical literature implicating the PDE5 inhibitors beginning in 2000 (see ref. 15-24).

After media coverage of the FDA announcement, Senator Charles Grassley became concerned about the lack of any substantive action by FDA and began his own investigation.[2] Grassley’s staff interviewed the safety evaluator from the FDA Office of Drug Safety (ODS), who had produced the original analysis of NAION in Viagra users. By monitoring adverse event reports submitted to the FDA, the safety evaluator had concluded, as early as January 2004, that NAION was an important safety issue for Viagra users. Her review had been sufficient to convince the deputy director of the Division of Anti-inflammatory, Analgesic, and Ophthalmic Drug Products that the potential for NAION should be added to the Viagra label. The NAION report was finalized in April 2004 and sent to the Office of New Drugs (OND), the final arbiter of label changes. Nevertheless, it wasn’t until July 8, 2005, 13 months after the Office of New Drugs received documents from the safety evaluator, that the FDA finally published safety alerts for patients and healthcare professionals on its web site.[3]

There is now mention of NAION in the Precautions and Adverse Reactions sections of the professional labels for Viagra, Cialis, and Levitra (but no mention anywhere in the label for Revatio). However, the wording is ambiguous and the location of this information is buried: under Information for Patients in the Precautions section (information that usually is not given to patients), there is one untitled paragraph. In the Adverse Reactions section under Post-marketing Experience, one of several paragraphs discusses NAION. In the case of Viagra, NAION is discussed in one of two paragraphs under Adverse Reactions subheaded “Special Senses” which gives no indication as to what is discussed (the other two drugs have paragraphs that are at least titled “Ophthalmologic”).

Emphasis in the label is on the word “rarely”, downplaying the importance of NAION and is coupled with the caveat that, “It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors”. It is probably true that many factors are involved, but one factor clearly seems to be the drug (see below).

The current label has a paragraph titled “Effects of VIAGRA on Vision” which includes no reference to NAION. This needs to be amended.

Public Citizen’s Analysis

Public Citizen has been concerned about a number of safety issues with Viagra’s use since its approval in 1998 when we asked the FDA to include stronger warnings concerning adverse effects.[4] Public Citizen had, at that time, only looked at the FDA reviews since no postmarketing adverse event data were available. Our concerns relating to the eye were limited to color aberrations, increased sensitivity to light, and blurred vision. However, after the publicity in May 2005 about NAION, we began reading the literature reports and decided to undertake our own analysis using the FDA Adverse Event Reports (AERS) database.

We used the search term “ischemic optic neuropathy” (ION) as recommended by a neuro-ophthalmologist (the term NAION is not present in the AERS database). We searched the entire FDA database from 1/1/98 to 12/31/04 for all reports of ION that showed up for any drug (combining brand and generic names). We found 258 reports in which a drug was listed as the primary suspect for this adverse event.

The three drugs with the highest percentage of reports of ION in the FDA’s AERS database were Viagra, interferon, and amiodarone (Table 1). These three drugs (of thousands in the data set) accounted for 42% of all reported ION cases. Viagra had the highest percentage by a factor of more than 2-fold in spite of the fact that during this time period there was no mention of NAION in the label, whereas the labels for both interferon and amiodarone had prominent Warnings and amiodarone had a statement in the Precautions section as well.[5] The fact that Viagra’s large numbers of adverse reaction reports occurred without any warnings to the medical profession strongly suggests that Viagra is an important factor in causing ION (all of these cases accrued before the Viagra-NAION association first came to public attention in May 2005). All reports are for Viagra, since Revatio had not been approved during the time period we searched.

Table 1. Ischemic optic neuropathy cases in the AERS database*

Counterfeit Versions of Cialis tablets identified entering the United States

FDA is alerting consumers and health care professionals that counterfeit versions of Cialis 20 mg tablets were found in the mail on its way to a U.S. consumer. While this shipment was stopped, FDA is concerned about other possible mail shipments to consumers. FDA laboratory analysis showed the counterfeit versions contain multiple active ingredients, which if used could result in adverse effects or harm. Consumers should only buy prescription medicines from state-licensed pharmacies located in the U.S.

FDA cannot confirm that the manufacturing, quality, storage, and handling of these products follow U.S. standards because these products are from an unknown source. Therefore, these products are considered unsafe and should not be used.

FDA also recommends consumers talk to their health care professional about their condition and options for treatment if they received a counterfeit product.

FDA-approved Cialis tablets made by Eli Lilly contain the active ingredient, tadalafil, and are used for the treatment of erectile dysfunction and other approved indications. Currently, Eli Lilly’s authentic product is considered safe and effective for its intended uses. There is no indication that the legitimate supply chain is at risk, therefore consumers can be confident that prescription medicines received through legitimate state-licensed pharmacies located in the U.S. are safe and effective.

Counterfeit versions of Cialis can be identified by the following differences on the label of the bottle when compared to the authentic product. The label:

lists “AUSTR81137” on the front of the bottle;
does not include an NDC number on the front of the bottle, such as “NDC 0002-4462-30” for the 20 mg tablets;
does not include the tablet strength in a colored box;
has different patterns and colors; it has yellow and darker green designs on the front label;
has misspellings; it lists, “CLALIS is a product of: Eli lilly Australia PTY Limited” on the side of the bottle;
lists the manufacturer location as “112 Wharf Road, WEST RYDE, NSW 2114” on the side of the bottle; and
lists “Lot: AC 066018, Exp: 01SEP17” on the side of the bottle.

Consumers should not use products that match one or more of the descriptions above. If you have additional information about these products, you may contact FDA at [email protected].

To date, FDA is not aware of consumer adverse events related to the use of these counterfeit versions of Cialis. Health care professionals and consumers are encouraged to report adverse events related to the use of any suspect medications to FDA’s MedWatch Adverse Event Reporting program by:

Consumers who buy prescription medicines online should be careful. Some websites sell medicine that may not be safe to use and may put their health at risk. Go to www.fda/gov/BeSafeRx for more information about the risks, to learn the signs of websites that may sell counterfeit or otherwise unsafe medicines, and how to find legitimate licensed online pharmacies.

FDA is committed to protecting public health by working to secure the drug supply chain against counterfeit and unapproved medications that enter the United States through fraudulent sources.

Picture of authentic bottle of Eli Lilly’s Cialis 20 mg Tablets sold in the U.S.

Cialis Side Effects Center

Cialis (tadalafil) is a phosphodiesterase inhibitor used for treating impotence (erectile dysfunction, or ED).

What Are Side Effects of Cialis?

flushing (redness or warmth of the face, neck, or chest),
headaches,
stomach upset,
diarrhea,
flu-like symptoms (such as stuffy nose, sneezing, or sore throat),
memory problems,
muscle or back pain,
nausea,
low blood pressure,
dizziness,
blurred vision and changes in color vision,
abnormal ejaculation, and
prolonged erections (priapism).

Tell your doctor if you have rare but serious side effects of Cialis including:

a painful or prolonged erection lasting 4 or more hours;
sudden decreased vision (including permanent blindness, in one or both eyes);
a sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness.

Cialis may cause serious side effects including:

chest pain,
pain spreading to the jaw or shoulder,
nausea,
sweating,
vision changes,
sudden vision loss,
ringing in your ears,
sudden hearing loss, and
an erection that is painful or lasts longer than 4 hours

Get medical help right away, if you have any of the symptoms listed above.

Seek medical care or call 911 at once if you have the following serious side effects:

Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheartedness, or passing out;
Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

Dosage for Cialis

The recommended dose of Cialis is 5-20 mg per day taken before sexual activity.

What Drugs, Substances, or Supplements Interact with Cialis?

Cialis may interact with rifamycins, antibiotics, antifungals, antidepressants, barbiturates, drugs to treat high blood pressure or a prostate disorder, heart or blood pressure medications, HIV or AIDS medications or seizure medications. Tell your doctor all medications and supplements you use.

Cialis During Pregnancy and Breastfeeding

Cialis is not approved for use in women and has not been evaluated in women who are breastfeeding.

Additional Information

Our Cialis Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

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.

QUESTION

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

Stop using tadalafil and call your doctor at once if you have:

heart attack symptoms–chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;
vision changes or sudden vision loss;
ringing in your ears or sudden hearing loss; or
an erection is painful or lasts longer than 4 hours (prolonged erection can damage the penis).

Stop and get medical help at once if you have nausea, chest pain, or dizziness during sex. You could be having a life-threatening side effect.

headache;
flushing (warmth, redness, or tingly feeling);
nausea, upset stomach;
runny or stuffy nose; or
muscle pain, back pain, pain in your arms, legs, or back.

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.

SLIDESHOW

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Tadalafil was administered to over 9000 men during clinical trials worldwide. In trials of CIALIS for once daily use, a total of 1434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. ForCIALIS for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year ,respectively.

CIALIS For Use As Needed For ED

In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to88) and the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%,compared to 1.4% in placebo treated patients.

When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported ( see Table 1) for CIALIS for use as needed:

Table 1: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with CIALIS (10or 20 mg) and More Frequent on Drug than Placebo in the Eight Primary Placebo-Controlled ClinicalStudies (Including a Study in Patients with Diabetes) for CIALIS for Use as Needed for ED

Adverse Reaction	Placebo (N=476)	Tadalafil 5 mg (N=151)	Tadalafil 10 mg (N=394)	Tadalafil 20 mg (N=635)
Headache	5%	11%	11%	15%
Dyspepsia	1%	4%	%	10%
Back pain	3%	3%	5%	6%
Myalgia	1%	1%	4%	3%
Nasal congestion	1%	2%	3%	3%
Flushing a	1%	2%	3%	3%
Pain in limb	1%	1%	3%	3%
a The term flushing includes: facial flushing and flushing

CIALIS For Once Daily Use For ED

In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82)and the discontinuation rate due to adverse events in patients treated with tadalafil was 4.1%, compared to 2.8%in placebo-treated patients.

The following adverse reactions were reported ( see Table 2) in clinical trials of 12 weeks duration:

Table 2: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with CIALIS forOnce Daily Use (2.5 or 5 mg) and More Frequent on Drug than Placebo in the Three Primary Placebo-Controlled Phase 3 Studies of 12 weeks Treatment Duration (Including a Study in Patients with Diabetes) for CIALIS for Once Daily Use for ED

Adverse Reaction	Placebo (N=248)	Tadalafil 2.5 mg (N=196)	Tadalafil 5 mg (N=304)
Headache	5%	3%	6%
Dyspepsia	2%	4%	5%
Nasopharyngitis	4%	4%	3%
Back pain	1%	3%	3%
Upper respiratory tract infection	1%	3%	3%
Flushing	1%	1%	3%
Myalgia	1%	2%	2%
Cough	0%	4%	2%
Diarrhea	0%	1%	2%
Nasal congestion	0%	2%	2%
Pain in extremity	0%	1%	2%
Urinary tract infection	0%	2%	0%
Gastroesophageal reflux disease	0%	2%	1%
Abdominal pain	0%	2%	1%

The following adverse reactions were reported ( see Table 3) over 24 weeks treatment duration in one placebo-controlled clinical study:

Table 3: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with CIALIS forOnce Daily Use (2.5 or 5 mg) and More Frequent on Drug than Placebo in One Placebo-ControlledClinical Study of 24 Weeks Treatment Duration for CIALIS for Once Daily Use for ED

Adverse Reaction	Placebo (N=94)	Tadalafil 2.5 mg (N=96)	Tadalafil 5 mg (N=97)
Nasopharyngitis	5%	6%	6%
Gastroenteritis	2%	3%	5%
Back pain	3%	5%	2%
Upper respiratory tract infection	0%	3%	4%
Dyspepsia	1%	4%	1%
Gastroesophageal reflux disease	0%	3%	2%
Myalgia	2%	4%	1%
Hypertension	0%	1%	3%
Nasal congestion	0%	0%	4%

CIALIS For Once Daily Use For BPH And For ED And BPH

In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with tadalafil was 3.6% compared to 1.6% in placebo-treated patients. adverse reactions leading to discontinuation reported by at least 2 patients treated with tadalafil included headache, upper abdominal pain, and myalgia. The following adverse reactions were reported ( see Table 4).

Table 4: Treatment-Emergent Adverse Reactions Reported by ≥1% of Patients Treated with CIALIS forOnce Daily Use (5 mg) and More Frequent on Drug than Placebo in Three Placebo-Controlled ClinicalStudies of 12 Weeks Treatment Duration, including Two Studies for CIALIS for Once Daily Use for BPHand One Study for ED and BPH

Adverse Reaction	Placebo (N=576)	Tadalafil 5 mg (N=581)
Headache	2.3%	4.1%
Dyspepsia	0.2%	2.4%
Back pain	1.4%	2.4%
Nasopharyngitis	1.6%	2.1%
Diarrhea	1.0%	1.4%
Pain in extremity	0.0%	1.4%
Myalgia	0.3%	1.2%
Dizziness	0.5%	1.0%

Across placebo-controlled studies with CIALIS for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with CIALIS (2.5% of patients) [see Use In Specific Populations] .

Across all studies with any CIALIS dose, reports of changes in color vision were rare (

Body as a Whole – asthenia, face edema, fatigue, pain, peripheral edema

Cardiovascular – angina pectoris, chest pain, hypotension, myocardial infarction, postural hypotension ,palpitations, syncope, tachycardia

Digestive – abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, GGTP increased, loose stools, nausea, upper abdominal pain, vomiting, gastroesophageal reflux disease, hemorrhoidal hemorrhage, rectal hemorrhage

Musculoskeletal – arthralgia, neck pain

Nervous – dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo

Renal and Urinary – renal impairment

Respiratory – dyspnea, epistaxis, pharyngitis

Skin and Appendages – pruritus, rash, sweating

Ophthalmologic – blurred vision, changes in color vision, conjunctivitis (including conjunctival hyperemia),eye pain, lacrimation increase, swelling of eyelids

Otologic – sudden decrease or loss of hearing, tinnitus

Urogenital – erection increased, spontaneous penile erection

Postmarketing Experience

The following adverse reactions have been identified during post approval use of CIALIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.

Cardiovascular And Cerebrovascular

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of CIALIS without sexual activity. Others were reported to have occurred hours to days after the use of CIALIS and sexual activity. It is not possible to determine whether these events are related directly to CIALIS, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors [see WARNINGS AND PRECAUTIONS] .

Body as a Whole – hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis

Nervous – migraine, seizure and seizure recurrence, transient global amnesia

Ophthalmologic – visual field defect, retinal vein occlusion, retinal artery occlusion

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including CIALIS. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking [see WARNINGS AND PRECAUTIONS] .

Otologic – Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including CIALIS. In some of the cases, medical conditions andother factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of CIALIS, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see WARNINGS AND PRECAUTIONS] .

Urogenital – priapism [see WARNINGS AND PRECAUTIONS] .

DRUG INTERACTIONS

Potential For Pharmacodynamic Interactions With CIALIS

Nitrates

Administration of CIALIS to patients who are using any form of organic nitrate, is contraindicated.In clinical pharmacology studies, CIALIS was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken CIALIS, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and CLINICAL PHARMACOLOGY] .

Alpha-Blockers

Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5inhibitors, including CIALIS, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, tamsulosin or alfuzosin. [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY] .

Anti hypertensives

PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood-pressure-lowering effects of selected anti hypertensive medications (amlodipine, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo. [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY] .

Alcohol

Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased.Substantial consumption of alcohol (e.g., 5 units or greater) in combination with CIALIS can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY] .

Potential For Other Drugs To Affect CIALIS

[See DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS] .

Antacids

Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.

H₂ Antagonists (e.g. Nizatidine)

An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.

Cytochrome P450 Inhibitors

CIALIS is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure.

Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4,increased tadalafil 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose exposure (AUC) by107% and Cmax by 15%, relative to the values for tadalafil 10 mg alone [see DOSAGE AND ADMINISTRATION] .

Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.

Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4,CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg single-dose exposure (AUC) by 32% with a 30%reduction in Cmax , relative to the values for tadalafil 20 mg alone. Ritonavir (200 mg twice daily), increased tadalafil 20-mg single-dose exposure (AUC) by 124% with no change in Cmax , relative to the values for tadalafil 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure [see DOSAGE AND ADMINISTRATION] .

Cytochrome P450 Inducers

Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure.

Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10-mg single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. No dose adjustment is warranted. The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of CIALIS for once daily use; the magnitude of decreased efficacy is unknown.

Potential For CIALIS To Affect Other Drugs

Aspirin

Tadalafil did not potentiate the increase in bleeding time caused by aspirin.

Cytochrome P450 Substrates

CIALIS is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil doe snot inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.

Tadalafil had no significant effect on the pharmacokinetics of theophylline.When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed.

Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin.

Tadalafil had no significant effect on exposure (AUC) to midazolamor lovastatin.

P-Glycoprotein (e.g. Digoxin)

Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.

Read the entire FDA prescribing information for Cialis (Tadalafil)

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Alyq Drug Imprint

Honey-based sexual supplements may contain Cialis and Viagra ingredients, FDA warns

The FDA sent warning letters to companies selling products with names like “Royal Honey for Him” and “X Rated Honey for Men” that may contain pharmaceuticals.

The Food and Drug Administration has issued warning letters to four companies selling honey-based supplements that claim to provide sexual enhancement.

The products, with names like “Royal Honey for Him” and “X Rated Honey for Men,” may contain hidden pharmaceuticals, the FDA said: the active ingredients in Cialis and Viagra.

In a release issued on July 12, the agency said that its internal lab testing found tadalafil and sildenafil in the honey products. Those ingredients, not listed on the labels, are found in Cialis and Viagra, which are used to treat erectile dysfunction and are only available by prescription.

These supplements might therefore pose health risks to consumers, the FDA said. The drugs can be dangerous for patients taking nitrates, which is common among those with diabetes, high cholesterol or heart disease, since the interaction could lead their blood pressure to drop to dangerously low levels. Other consumers might have allergies or sensitivities to the medications.

Adding a drug into a food product for interstate commerce violates federal law, the FDA said. The agency gave the companies 15 days to either state how they will address the problem or explain why they believe the products do not violate the law. If they do not respond, they risk seizure, injunction or a referral to the FDA’s Office of Criminal Investigations, an agency spokesperson said.

The companies that received FDA letters are Thirsty Run LLC (also known as US Royal Honey LLC), 1am USA Incorporated dba Pleasure Products USA, Shopaax.com and MKS Enterprise LLC.

Two of the four did not respond to requests for comment. Shopaax.com on Wednesday pointed NBC News to its the recall notice for the product the site sells, called “Kingdom Honey Royal Honey VIP.” Then on Tuesday, MKS Enterprise told NBC News that it will be recalling its product, “Dose Vital VIP Vital Honey.”

Other honey products mentioned in the FDA’s warnings include “Vital Honey for Men” and “Secret Miracle Royal Honey for Her.” According to the FDA, the products are sold online and possibly in some retail stores.

The supplements generally claim to provide sexual enhancement and boost reproductive health.

The product description of “Royal Honey for Men,” for example, says it is made using “the most potent and natural source of sexual power and testosterone—Royal Honey—that is filled with rich floral nectar and a mix of select roots to maximize the effect.”

The ingredients listed for that product include ginseng root and tribulus terrestris, a leafy plant.

“People should be very leery taking many of the products and supplements, because they’re unregulated, and most people don’t know what’s actually in them,” said Dr. Franklin Lowe, vice chairman of the Department of Urology at Montefiore Medical Center and a professor at Albert Einstein School of Medicine.

“What is on the label doesn’t necessarily correlate to what’s actually in the bottle or in the pill. And this is a perfect example of that,” he added.

Because dietary supplements are regulated as food, not drugs, the FDA does not vet them for safety, effectiveness or labeling, nor give them federal approval.

Other sexual enhancement supplements have similarly been found to be hiding active drug ingredients in the past.

The FDA warned consumers in April about nearly a dozen other honey-based sexual supplements that contained drug ingredients. In 2019, the FDA announced that sexual enhancement pills sold on websites including Amazon contained hidden and potentially dangerous ingredients like sildenafil.

An FDA spokesperson said the agency has been issuing alerts about tainted sexual enhancement supplements since at least 2007. Its first alert about honey-based products was in 2017.

“We encourage consumers to remain vigilant when shopping online or in stores to avoid purchasing products that put their health at risk, and instead seek effective, FDA-approved treatments,” Judy McMeekin, the FDA’s associate commissioner for regulatory affairs, said in the release.

Elliot Lewis is an intern for NBC News.

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Last updated on emc: 08 Oct 2021

What is a Patient Information Leaflet and why is it useful?

The Patient Information Leaflet (PIL) is the leaflet included in the pack with a medicine. It is written for patients and gives information about taking or using a medicine. It is possible that the leaflet in your medicine pack may differ from this version because it may have been updated since your medicine was packaged.

Below is a text only representation of the Patient Information Leaflet. The original leaflet can be viewed using the link above.

The text only version may be available in large print, Braille or audio CD. For further information call emc accessibility on 0800 198 5000. The product code(s) for this leaflet is: PLGB 14895/0238.

Package leaflet: Information for the user

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

1. What CIALIS is and what it is used for
2. What you need to know before you take CIALIS
3. How to take CIALIS
4. Possible side effects
5 How to store CIALIS
6. Contents of the pack and other information

1. What CIALIS is and what it is used for

CIALIS is a treatment for adult men with erectile dysfunction. This is when a man cannot get, or keep a hard, erect penis suitable for sexual activity. CIALIS has been shown to significantly improve the ability of obtaining a hard erect penis suitable for sexual activity.

CIALIS contains the active substance tadalafil which belongs to a group of medicines called phosphodiesterase type 5 inhibitors. Following sexual stimulation CIALIS works by helping the blood vessels in your penis to relax, allowing the flow of blood into your penis. The result of this is improved erectile function. CIALIS will not help you if you do not have erectile dysfunction.

It is important to note that CIALIS does not work if there is no sexual stimulation. You and your partner will need to engage in foreplay, just as you would if you were not taking a medicine for erectile dysfunction.

2. What you need to know before you take CIALIS

are allergic to tadalafil or any of the other ingredients of this medicine (listed in section 6).
are taking any form of organic nitrate or nitric oxide donors such as amyl nitrite. This is a group of medicines (“nitrates”) used in the treatment of angina pectoris (“chest pain”). CIALIS has been shown to increase the effects of these medicines. If you are taking any form of nitrate or are unsure tell your doctor.
have serious heart disease or recently had a heart attack within the last 90 days.
recently had a stroke within the last 6 months.
have low blood pressure or uncontrolled high blood pressure.
ever had loss of vision because of non-arteritic anterior ischemic optic neuropathy (NAION), a condition described as “stroke of the eye”.
are taking riociguat. This drug is used to treat pulmonary arterial hypertension (i.e., high blood pressure in the lungs) and chronic thromboembolic pulmonary hypertension (i.e., high blood pressure in the lungs secondary to blood clots). PDE5 inhibitors, such as CIALIS, have been shown to increase the hypotensive effects of this medicine. If you are taking riociguat or are unsure tell your doctor.

Talk to your doctor before taking CIALIS.

Be aware that sexual activity carries a possible risk to patients with heart disease because it puts an extra strain on your heart. If you have a heart problem you should tell your doctor.

Before taking the tablets, tell your doctor if you have:

sickle cell anaemia (an abnormality of red blood cells).
multiple myeloma (cancer of the bone marrow).
leukaemia (cancer of the blood cells).
any deformation of your penis.
a serious liver problem.
a severe kidney problem.

It is not known if CIALIS is effective in patients who have had:

pelvic surgery.
removal of all or part of the prostate gland in which nerves of the prostate are cut (radical non-nerve-sparing prostatectomy).

If you experience sudden decrease or loss of vision, stop taking CIALIS and contact your doctor immediately.

Decreased or sudden hearing loss has been noted in some patients taking tadalafil. Although it is not known if the event is directly related to tadalafil, if you experience decreased or sudden hearing loss, stop taking CIALIS and contact your doctor immediately.

CIALIS is not intended for use by women.

CIALIS is not intended for use by children and adolescents under the age of 18.

Tell your doctor if you are taking, have recently taken or might take any other medicines

Do not take CIALIS if you are already taking nitrates.

Some medicines may be affected by CIALIS or they may affect how well CIALIS will work. Tell your doctor or pharmacist if you are already taking:

an alpha blocker (used to treat high blood pressure or urinary symptoms associated with benign prostatic hyperplasia).
other medicines to treat high blood pressure.
riociguat.
a 5- alpha reductase inhibitor (used to treat benign prostatic hyperplasia).
medicines such as ketoconazole tablets (to treat fungal infections) and protease inhibitors for treatment of AIDS or HIV infection.
phenobarbital, phenytoin and carbamazepine (anticonvulsant medicines).
rifampicin, erythromycin , clarithromycin or itraconazole.
other treatments for erectile dysfunction.

Information on the effect of alcohol is in section 3. Grapefruit juice may affect how well CIALIS will work and should be taken with caution. Talk to your doctor for further information.

When dogs were treated there was reduced sperm development in the testes. A reduction in sperm was seen in some men. These effects are unlikely to lead to a lack of fertility.

Some men taking CIALIS in clinical studies have reported dizziness. Check carefully how you react to the tablets before driving or using machines.

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

CIALIS tablets are for oral use in men only. Swallow the tablet whole with some water. The tablets can be taken with or without food.

The recommended starting dose is one 10 mg tablet before sexual activity. However, you have been given the dose of one 20mg tablet as your doctor has decided that the recommended dose of 10mg is too weak.

You may take a CIALIS tablet at least 30 minutes before sexual activity.

CIALIS may still be effective up to 36 hours after taking the tablet.

Do not take CIALIS more than once a day. CIALIS 10 mg and 20 mg is intended for use prior to anticipated sexual activity and is not recommended for continuous daily use.

Drinking alcohol may affect your ability to get an erection and may temporarily lower your blood pressure. If you have taken or are planning to take CIALIS, avoid excessive drinking (blood alcohol level of 0.08 % or greater), since this may increase the risk of dizziness when standing up.

If you take more CIALIS than you should

Contact your doctor. You may experience side effects described in section 4.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everybody gets them. These effects are normally mild to moderate in nature.

If you experience any of the following side effects stop using the medicine and seek medical help immediately:

allergic reactions including rashes (frequency uncommon).
chest pain – do not use nitrates but seek immediate medical assistance (frequency uncommon).
priapism, a prolonged and possibly painful erection after taking CIALIS (frequency rare). If you have such an erection, which lasts continuously for more than 4 hours you should contact a doctor immediately.
sudden loss of vision (frequency rare).

Common (seen in 1 to 10 in every 100 patients)

Uncommon (seen in 1 to 10 in every 1,000 patients)

dizziness, stomach ache, feeling sick, being sick (vomiting), reflux, blurred vision, eye pain, difficulty in breathing, presence of blood in urine, prolonged erection, pounding heartbeat sensation, a fast heart rate, high blood pressure, low blood pressure, nose bleeds, ringing in the ears, swelling of the hands, feet or ankles and feeling tired.

Rare (seen in 1 to 10 in every 10,000 patients)

fainting, seizures and passing memory loss, swelling of the eyelids, red eyes, sudden decrease or loss of hearing, hives (itchy red welts on the surface of the skin), penile bleeding, presence of blood in semen and increased sweating.

Heart attack and stroke have also been reported rarely in men taking CIALIS. Most of these men had known heart problems before taking this medicine.

Partial, temporary, or permanent decrease or loss of vision in one or both eyes has been rarely reported.

Some additional rare side effects have been reported in men taking CIALIS that were not seen in clinical trials. These include:

migraine, swelling of the face, serious allergic reaction which causes swelling of the face or throat, serious skin rashes, some disorders affecting blood flow to the eyes, irregular heartbeats, angina and sudden cardiac death.

The side effect dizziness has been reported more frequently in men over 75 years of age taking CIALIS. Diarrhoea has been reported more frequently in men over 65 years of age taking CIALIS.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after ‘EXP’. The expiry date refers to the last day of that month.

Store in the original package in order to protect from moisture. Do not store above 30°C.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

The active substance is tadalafil. Each tablet contains 20 mg of tadalafil.
The other ingredients are:
Tablet core: lactose monohydrate (see end of section 2), croscarmellose sodium, hydroxypropylcellulose, microcrystalline cellulose, sodium laurilsulfate, magnesium stearate, see section 2 “CIALIS contains lactose”.
Film-coat: lactose monohydrate, hypromellose, triacetin, titanium dioxide (E171), iron oxide yellow (E172), talc.

What CIALIS looks like and contents of the pack

CIALIS 20 mg is a yellow film-coated tablet in the shape of an almond and has “C 20” marked on one side.

CIALIS 20 mg is available in blister packs containing 2, 4, 8, 10 or 12 tablets.

Marketing Authorisation Holder and Manufacturer

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

This leaflet was last revised in January 2021.