When Rx-to-OTC Switch Medications Become Generic

US Pharm.2008;33(6)(Generic Drug Review suppl):20-27.

There is little debate that the Rx-to-OTC switch movement (when a prescription drug is reclassified to nonprescription or OTC status) has caused major changes in the pharmacy marketplace. When the patent on a prescription medication expires, the manufacturer typically experiences a dip in profits due to emerging competition from generics. Moving a prescription drug to nonprescription status does not automatically confer increased patent life. However, if the FDA requires the manufacturer to carry out additional studies via a supplemental new drug application to demonstrate safety and/or efficacy for the proposed switch, the manufacturer can gain as much as three years of patent exclusivity. Eventually, though, even the extended patent protection expires, and the medication often becomes available as a generic.

The Pharmacist's Dilemma with OTC Medications
Pharmacy students are taught to recommend nonprescription or OTC products to patients on the basis of two fundamentally important parameters--safety and efficacy. Cost considerations often take a backseat. However, the pharmacist counseling a patient often notices that a discussion of the optimal nonprescription product for a minor health care condition eventually turns to the cost of the recommended product. The pharmacist may recommend the most appropriate OTC product on the basis of safety and efficacy, as he or she was taught, only to watch helplessly as the price-conscious patient chooses a less appropriate product, solely because it is less expensive than the one recommended. For this reason, it is helpful to the pharmacist when OTC medications are marketed generically, as narrowing price gaps between therapeutic options allow the patient to choose the most safe and effective product.

Advantages of OTC or Nonprescription Generics
The chief benefit to patients when a nonprescription medication becomes available generically is identical to the situation with prescription medications: prices for generic OTC versions are lower than those for the branded products. The savings vary from product to product, but they can be as little as 11% (some omeprazole generics) to over 75% (some loratadine generics).¹ For the price-conscious patient, the cost savings can be critical in making self-care decisions. Further, for the price-sensitive patient with a chronic, self-treatable medical condition, the addition of a new generic OTC with that indication expands the range of therapeutic options.

Frequently, the newer generic OTC medication possesses unique advantages that make it a better choice for many patients. This is illustrated by the gradually increasing group of options for allergic rhinitis. At one time, the patient with allergic rhinitis had little to choose from other than older (first-generation) antihistamines. When loratadine (Claritin) and cetirizine (Zyrtec) switched to OTC status, their contraindications for self-treating patients differed from those pertaining to first-generation antihistamines. These second-generation antihistamines were not inexpensive when first introduced. However, when they became generic, price-conscious patients could choose them for their unique advantages and lower price.

Drugs transferred from Rx-to-OTC status by the FDA since 2000 are listed in TABLE 1.² This review will focus on three major categories: antihistamines that treat allergic rhinitis, acid reducers for heartburn/indigestion, and smoking cessation products.

Allergic Rhinitis
Brompheniramine and chlorpheniramine became the first nonprescription antihistamines when the FDA approved their OTC sale in 1976.² Dexbrompheniramine and triprolidine followed in 1982, diphenhydramine (Benadryl) in 1985, doxylamine in 1987, and clemastine (Tavist) and dexchlorpheniramine in 1992.² By 1992, the pantheon of nonprescription first-generation antihistamines was completed.

First-generation antihistamines are grouped together because they share several characteristics. One is the list of contraindications for their safe self-use. They should not be used without physician supervision if the patient has any of the following: emphysema, chronic bronchitis, glaucoma, or difficulty in urination due to enlargement of the prostate gland.³ Further, all were clearly contraindicated for self-administration in patients under the age of 6 years to avoid excitability, despite patient dosing charts marketed by several companies that recommended their use in children as young as 6 months without FDA proof of safety and efficacy.³ Their labels cautioned against use with sedatives or tranquilizers without first speaking to a doctor or pharmacist. They cautioned that drowsiness might occur (marked drowsiness with diphenhydramine) and cautioned against concomitant use with alcohol or when driving or operating heavy machinery.

In 2002, the FDA approved the nonprescription sale of Claritin. It became available generically as loratadine within a few years.² In 2007, a switch for Zyrtec was approved, and generic cetirizine became available in 2008.² These drugs are referred to as second-generation antihistamines for several reasons. Foremost is the fact that they are safe for self-use in patients with emphysema, chronic bronchitis, glaucoma, and difficulty in urination due to enlargement of the prostate gland. Thus, the price-conscious patient with these medical conditions who wished to use a generically available antihistamine was able to purchase loratadine and cetirizine when they became available generically. However, they should not be used by patients with liver or kidney disease without first speaking to a physician.³

The second-generation antihistamines also brought another large benefit to price-conscious patients when they became available generically. Loratadine syrup can be given to children as young as 2 years of age, greatly extending the ability of parents to safely treat children with allergic rhinitis.³ Eventually, cetirizine syrup may also be available generically. As Children's Zyrtec Allergy Syrup carries labeling for children as young as 2 years, it can be predicted that the generic version will also carry this labeling.⁴

Generic availability of loratadine and cetirizine brings another benefit to price-conscious patients. They are widely considered to be nonsedating. The patient who must drive or operate heavy machinery was once locked into the more sedating first-generation antihistamines. That is no longer the case, as loratadine and cetirizine are less likely to cause drowsiness. Loratadine also does not carry the warnings against use when driving or operating heavy machinery or use with alcohol, sedatives, or tranquilizers.³

However, it should be noted that the product labels of both cetirizine and loratadine caution that drowsiness may occur when taking normal doses (cetirizine) or when taking more than directed (loratadine).^3,5 Further, cetirizine carries the same warnings as first-generation antihistamines in regard to use of alcohol, sedatives, and tranquilizers and when driving or operating heavy machinery. ⁵

Another option for allergic rhinitis is NasalCrom Nasal Spray.³ Currently, there is no generic version available. However, if it is ever marketed, the generic OTC product would also present unique advantages in regard to contraindications and other considerations that may be important to the price-conscious patient.

Heartburn and Acid Indigestion
Prior to 1995, the patient with heartburn, acid indigestion, or sour stomach had little choice for self-treatment except nonprescription antacids and antirefluxants. These products were limited in their method of action and by their adverse reactions. Those containing calcium (e.g., Tums) caused constipation, while those containing magnesium (e.g., Milk of Magnesia) were more prone to cause diarrhea.⁶ Products with magnesium were not for self-treatment without physician advice if the patient had kidney disease. Those with sodium (e.g., Alka-Seltzer) were not to be used by patients on sodium-restricted diets without physician advice. Antirefluxants (e.g., Gaviscon) allegedly prevented reflux through the creation of a "raft" of nonirritating alginate that supposedly floated atop the stomach contents to prevent more irritating materials from being refluxed.⁶ Antacids and antirefluxants only neutralized acid that had already been produced, greatly limiting their utility.

This nonprescription market changed radically with the Rx-to-OTC switch of the histamine-2 (H2) blocking agents famotidine (Pepcid AC) and cimetidine (Tagamet HB) in 1995, and ranitidine (Zantac 75) and nizatidine (Axid AR) in 1996.² The first three OTC products are available generically. Rather than simply neutralizing acid that has already been produced, the H2 blockers prevent acid production, making them more powerful medications for heartburn, acid indigestion, and sour stomach. They should not be taken by those aged under 12 years or taken more than two weeks after onset of symptoms.⁶ They can be used to treat active symptoms, as well as to prevent symptoms. They should not be used with other acid reducers.

This market again changed radically when the proton pump inhibitor (PPI) omeprazole (Prilosec OTC) was given the green light for a switch by the FDA in 2003, and again when it recently became available in a generic form.² PPIs are generally considered to be more effective than either antacids or H2 blockers, so its generic availability was an advance for the price-conscious patient. Omeprazole is the only product currently FDA approved for frequent heartburn that occurs on two or more days per week. (For less frequent heartburn, the patient might try H2 blockers or antacids.) Omeprazole does not provide immediate relief. It may take one to four days for the patient to gain the full effect.⁶ Patients take one tablet with a full glass of water every 24 hours, in the morning before eating, for 14 consecutive days. The patient cannot repeat this regimen more often than every four months. Any patient who feels the need to take it beyond 14 days in a row or more than every four months should be counseled to visit a physician instead. Those under the age of 18 years should not take omeprazole.⁶

Patients taking omeprazole should be told that it does not provide immediate relief. Patients may not notice the full effect for one to four days, although some do obtain complete relief within 24 hours. It should not be recommended if the patient has an allergy to omeprazole, trouble or pain when swallowing food, vomiting of blood, or bloody or black stools. Patients should consult a physician before taking it if they have any of the following: heartburn that has persisted for more than three months; heartburn along with lightheadedness, sweating or dizziness; chest or shoulder pain with shortness of breath, sweating, pain that spreads to the arms/neck/shoulders, or lightheadedness; frequent chest pain; frequent wheezing, particularly with heartburn; unexplained weight loss; nausea or vomiting; and stomach pain. Patients should consult a pharmacist or physician before taking omeprazole if they are also taking warfarin, prescription antifungal or antiyeast medications, diazepam, or digoxin.⁶

Smoking Cessation

Before 1996, there had never been a safe and effective nonprescription product for smoking cessation. Several herb-based and homeopathic products had been marketed and are still being marketed, but their safety and efficacy have never been established. The nonprescription smoking cessation market gained its first safe and effective product in 1996 with FDA approval to switch nicotine polacrilex gum (Nicorette) to nonprescription status.² The market expanded in 1996 with the approval of nonprescription transdermal patches.² The final dosage form, the nicotine lozenge, was approved for OTC sale in 2002. ² At this time, all are available generically.

The OTC smoking cessation products all share some important warnings. They cannot be sold legally to those under the age of 18 years, and they cannot be placed in a vending machine or any other location where the age of the purchaser cannot be verified. They are not safe for the pregnant or breastfeeding patient, as they can cause tachycardia in the infant. Rather, the pharmacist should urge these patients to attempt smoking cessation without the products. They must not be used if the patient will continue to smoke, chew tobacco, or use snuff. They cannot be combined with each other and should not be used with prescription smoking cessation therapies unless a physician advises them to do so.⁷

Patients should not use smoking cessation products without physician advice if they have heart disease or irregular heartbeat, or have experienced a recent heart attack, as they can increase the heart rate. They should not use them without physician advice if they have hypertension uncontrolled by medication, as nicotine can increase blood pressure. They should speak to a physician or pharmacist before use if they are taking prescription medications for depression or asthma, as nicotine can alter the response to theophylline or imipramine through its enzyme-inducing properties. They should stop use and speak to a physician if they develop irregular heartbeat or palpitations, symptoms of nicotine overdose (e.g., nausea, vomiting, dizziness, weakness, tachycardia), or diarrhea with the gum and lozenge products.⁷

Nicotine gum and lozenges should not be used in patients with stomach ulcers because they may delay healing. Similarly, they should be avoided in patients with diabetes as they promote hyperinsulinemia, leading to insulin resistance. Nicotine transdermal patches should be avoided by patients with allergies to adhesive tape or with skin problems such as atopic dermatitis.⁷

Conclusion
When medications switch from prescription to nonprescription status (the Rx-to-OTC switch), patients benefit greatly. Price-conscious patients can realize these benefits when the OTC medication also becomes available generically. Generic availability of recently switched products for heartburn, allergic rhinitis, and smoking cessation is illustrative of the expanding range of treatment options available to price-sensitive patients.

REFERENCES
1. Omeprazole. Loratadine. www.drugstore.com. Accessed May 5, 2008.

2. Ingredients and dosages transferred from Rx-to-OTC status (or new OTC approvals) by the Food and Drug Administration since 1975. Consumer Healthcare Products Association. November 20, 2007. www.chpa-info.org/NR/rdonlyres/E33F414C-24FE-4F34-B6FD-149D16DCE2FA/0/switch_list112007.pdf. Accessed April 21, 2008.

3. Pray WS. Allergic rhinitis. In: Pray WS, ed. Nonprescription Product Therapeutics. 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006:219-234.

4. Children's Zyrtec Allergy Syrup (cetirizine) package insert. Fort Washington, PA: McNeil-PPC, Inc; 2007.

5. Zyrtec Tablets (cetirizine) package insert. Fort Washington, PA: McNeil-PPC, Inc; 2007.

6. Pray WS. Gastric distress. In: Pray WS, ed. Nonprescription Product Therapeutics. 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006:81-105.

7. Pray WS. Nicotine addiction. In: Pray WS, ed. Nonprescription Product Therapeutics. 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006:736-748.

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