Forms, strengths, for sleep, and more

Ativan (lorazepam) is a prescription brand-name medication. The Food and Drug Administration (FDA) has approved it to:

• treat sleep problems caused by anxiety or stress
• treat certain seizures
• treat anxiety
• make you fall asleep before surgery

Ativan contains the active drug lorazepam and belongs to a drug class called benzodiazepines. Lorazepam is also the name of the generic form of Ativan.

Ativan comes as oral tablets and injections.

For information about the dosage of Ativan, including its forms, strengths, and how to take the medication, keep reading. For a comprehensive look at Ativan, see this article.

This article describes typical dosages for Ativan provided by the drug’s manufacturer. When taking Ativan, always follow the dosage prescribed by your doctor.

If your doctor prescribes Ativan, you may have questions about the drug’s dosage, such as:

• What’s Ativan’s dosage range?
• What are the usual dosage amounts of Ativan?
• What’s considered a safe dose of Ativan?

Below is a basic dosage chart for Ativan (“mg” refers to milligrams).

Ativan forms and strengths

Ativan comes as oral tablets and a vial that contains a liquid solution. The solution is given as an intravenous (IV) injection or intramuscular (IM) injection.

Here are the strengths for each form of Ativan:

• Oral tablets: 0.5 mg, 1 mg, 2 mg
• Liquid solution for injection: 2 mg per 1 milliliter (mL) of liquid solution (2 mg/mL), 4 mg/mL

Typical dosages

Depending on what you’re taking Ativan to treat and the dosage form your doctor prescribes, they may start you on a low dosage. Then they may adjust it over time to reach the amount that’s right for you. Your doctor will ultimately prescribe the smallest dosage that provides the desired effect.

The following information describes dosages that are commonly taken or recommended. However, be sure to take the dosage your doctor prescribes for you. Your doctor will determine the best dosage to fit your needs.

Dosage for sleep problems caused by anxiety or stress

To treat sleep problems caused by anxiety or stress, your doctor will prescribe Ativan tablets. The dosage range for this use is 2 mg to 4 mg once per day, taken at bedtime.

Dosage for certain seizures

To treat certain seizures, a healthcare professional will typically give you Ativan as an IV injection. In some cases, they may give you an IM injection.

The usual dosage is 4 mg given slowly (about 2 minutes). If the seizures continue after 10 to 15 minutes, you may be given another 4-mg dose.

Dosage for anxiety

To treat anxiety, your doctor will prescribe Ativan tablets. The dosage range for this use is 1 mg to 10 mg, which is usually split into two or three doses per day.

The typical dose is 2 mg to 6 mg, divided into two or three doses per day. For example, if your daily dosage is 4 mg, you would take 2 mg once in the morning and once in the evening.

Dosage for surgery

To make you sleep before surgery, a healthcare professional will typically give you an IM injection of Ativan.

For this use, Ativan is dosed based on body weight. You’ll likely receive an IM injection of 0.05 mg per kilogram (kg) of body weight, up to a maximum dose of 4 mg. (One kilogram equals about 2.2 pounds.)

Ativan may also be given by IV injection to make you sleep before surgery. The recommended dose for this use is either 2 mg or 0.02 mg per pound (0.044 mg/kg) of body weight, whichever is smaller.

The healthcare professional will determine what dose is right for you.

Long-term use

Using Ativan for more than 4 months in a row hasn’t been studied. Ativan is not meant to be taken as a long-term treatment. Your doctor will typically check from time to time whether you still need to take Ativan.

Children’s dosage

Ativan is not approved for children to take. The drug has not proven to be safe and effective to treat conditions in this group.

The maximum dose of Ativan in 24 hours is 10 milligrams (mg). This dose is typically taken for conditions that are treated with Ativan tablets, such as anxiety.

The 10-mg maximum dose is usually divided into two or three doses. For example, you may take 2 mg in the morning, 2 mg in the afternoon, and 6 mg before bed.

For making you sleep before surgery, the maximum dose of Ativan is 4 mg.

For more information about Ativan dosages, including what’s a safe dose of Ativan, see the “Ativan dosage” section just above.

Below are answers to some frequently asked questions about Ativan dosages.

What’s considered a ‘normal’ dosage of Ativan?

The “normal” (usual) dosage of Ativan is 2 milligrams (mg) to 6 mg total, divided into two or three doses. For example, to treat anxiety, you may take Ativan tablets at a dosage of 2 mg twice per day, for a total daily dosage of 4 mg.

For more information about Ativan dosages, including what’s a safe dose of Ativan, see the “Ativan dosage” section above. You can also speak with your doctor or pharmacist.

What’s the Ativan dosage for panic and anxiety attacks?

Ativan is not approved to treat panic or anxiety attacks. But the drug may be prescribed off-label for this use. Off-label use is when a drug is prescribed to treat a condition it isn’t approved to treat.

To learn more about using Ativan for panic or anxiety attacks and what the dosage would be, talk with your doctor or pharmacist.

Is Ativan used for dogs? If so, what’s the dosage for dogs?

Ativan is not approved for use in dogs, but your veterinarian might recommend Ativan for your dog in some situations. Ativan may be used in dogs to help reduce anxiety or stress, to sedate your dog during a surgery, or to treat seizures.

Do not give your dog Ativan unless your veterinarian recommends this. Your veterinarian can recommend whether this drug is safe for your dog and what dosage your dog might need. If you think your pet has eaten your Ativan medication, contact your veterinarian right away.

The Ativan dosage your doctor prescribes will depend on several factors. These include:

• the type and severity of the condition you’re using Ativan to treat
• the form of Ativan you take
• your age
• your body weight, depending on the form of the drug and what it’s treating

Other medical conditions you have can also affect your Ativan dosage.

Dosage adjustments

If you’re an older adult, you may need a lower dose of Ativan than usual. This is because Ativan affects your body differently as you age.

You may also need a dosage adjustment if you have kidney or liver problems. Your doctor will typically decrease your dose based on the severity of your liver or kidney condition.

Your doctor or pharmacist can tell you more about Ativan dosage adjustments.

How you take Ativan depends on the form of the drug you’re prescribed.

One form is oral tablets that you swallow. You can take them with or without food.

Ativan’s other form is a liquid solution that’s given as an intravenous (IV) injection or intramuscular injection. A healthcare professional will give you Ativan injections.

Be sure to take Ativan exactly as your doctor prescribes. You should not take more or less Ativan than prescribed without first speaking with them.

If you miss a dose of Ativan, take it as soon as you remember. But if it’s almost time for your next dose, skip the missed dose. Then take your next dose at your regular scheduled time.

You should not take more than one dose to try and make up for the missed dose. This can increase your risk for side effects from Ativan. (For more about Ativan’s side effects, see this article.)

To help make sure that you do not miss a dose, try using a medication reminder. This can include setting an alarm or timer on your phone or downloading a reminder app. A kitchen timer can work, too.

Ativan has a boxed warning regarding misuse and addiction. A boxed warning is the most serious warning given to a medication by the Food and Drug Administration (FDA). It alerts doctors and patients about drug effects that may be dangerous.

Taking Ativan can lead to misuse and addiction, even when you take an approved dosage. Misusing Ativan can cause serious side effects such as trouble breathing or coma. This risk increases if you take Ativan with certain other drugs or substances, including alcohol. Although rare, misusing Ativan can be fatal.

Misusing Ativan can also increase your risk for overdose. (To learn more, see the “Ativan and overdose” section below.

Because of the risk for misuse, Ativan is a controlled substance. This means its use is regulated by the government to prevent possible misuse. You should not share your Ativan prescription with anyone else. Be sure to take Ativan exactly as your doctor prescribes.

Also, it’s recommended that you store Ativan in a safe place, away from children.

If you take more Ativan than your doctor prescribes, you may develop serious side effects.

It’s important that you do not take more Ativan than your doctor advises.

Symptoms of an overdose

Overdose symptoms of Ativan can include:

• confusion
• drowsiness
• low blood pressure
• problems with coordination or balance
• slowed reflexes
• coma
• in rare cases, death

If you take more than the recommended amount of Ativan

Call your doctor right away if you believe you’ve taken too much Ativan. Another option is to call the American Association of Poison Control Centers at 800-222-1222 or use its online tool. If you have severe symptoms, immediately call 911 or your local emergency number, or go to the nearest emergency room.

Ativan has a boxed warning regarding physical dependence and withdrawal. A boxed warning is the most serious warning given to a medication by the Food and Drug Administration. It alerts doctors and patients about drug effects that may be dangerous.

Using Ativan can lead to physical dependence. This could lead to withdrawal if you suddenly stop taking the drug, even if you take an approved dosage.

You should not suddenly stop taking Ativan. Doing so could cause serious or, rarely, life-threatening side effects that can include:

• seizures
• unusual movements, expressions, or responses
• depression
• hallucinations (seeing or hearing things that aren’t there)
• losing touch with reality

In some people, withdrawal symptoms from benzodiazepines such as Ativan can cause symptoms that last for up to 12 months, such as:

• anxiety
• trouble remembering or concentrating
• depression
• trouble sleeping
• feeling like insects are crawling under your skin
• muscle weakness or twitching
• tinnitus (ringing in your ears)

Instead of suddenly stopping Ativan treatment, your doctor will help you with a drug taper. This involves gradually lowering the dosage of the medication over time. A drug taper can help decrease your risk for withdrawal symptoms or make them less severe.

If you’re interested in stopping treatment with Ativan, be sure to talk with your doctor first. You should not suddenly stop taking the drug on your own.

The dosages in this article are typical dosages provided by the drug manufacturer. If your doctor recommends Ativan for you, they will prescribe the dosage that’s right for you. Always follow the dosage that your doctor prescribes for you.

As with any drug, never change your dosage of Ativan without your doctor’s recommendation. If you have questions about the dosage of Ativan that’s right for you, talk with your doctor.

Besides learning about dosage, you may want other information about Ativan. These additional articles might be helpful:

• More about Ativan. For information about other aspects of Ativan, refer to this article.
• Drug comparison. To find out how Ativan compares with Xanax, read this article.
• Side effects. To learn about side effects of Ativan, see this article. You can also look at the prescribing information for Ativan tablets and solution.
• Interactions. For details about what Ativan interacts with, see this article.
• Details about your condition. For details about sleep problems, refer to our sleep hub and list of sleep articles. For more information about mental health and anxiety, see our mental health hub and list of anxiety articles. To learn more about the other conditions Ativan is prescribed for, talk with your doctor.

Disclaimer: Medical News Today has made every effort to make certain that all information is factually correct, comprehensive, and up to date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or another healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.

Forms, Strengths, How It’s Used, and More

If you have seizures, anxiety, trouble sleeping, or an upcoming surgery, your doctor might suggest Ativan as a treatment option for you. It’s a prescription drug used in adults to:

• treat certain seizures
• make you fall asleep before surgery
• treat anxiety
• treat insomnia (trouble sleeping) due to anxiety or stress

The active ingredient in Ativan is lorazepam. (An active ingredient is what makes a drug work. ) It belongs to a group of drugs called benzodiazepines.

Ativan comes as a tablet that you swallow. It also comes as a liquid solution given as an injection by your doctor. With this form, you’ll either receive your dose by intramuscular (IM) injection, which is an injection into a muscle, or by intravenous (IV) injection, which is an injection into a vein.

This article describes the dosages of Ativan, as well as its strengths and how to take it. To learn more about Ativan, see this in-depth article.

This chart highlights the basics of Ativan’s dosages. Be sure to read on for more detail.

Please keep in mind that this article covers Ativan’s standard dosage schedule, which is provided by the drug’s manufacturer. But always follow the dosing instructions your doctor prescribes.

Note: Because of Ativan’s risk of misuse, the drug is a controlled substance. This means its use is regulated by the government to prevent possible misuse. You should not share your Ativan prescription with anyone else. And be sure to take Ativan exactly as your doctor prescribes. It’s also recommended that you store Ativan in a safe place, away from children.

Read more about Ativan’s dosage in this section.

What are the forms of Ativan?

Ativan comes as a tablet that you swallow. It also comes as a liquid solution that you’ll receive as an injection into a vein or muscle from your doctor.

What strengths does Ativan come in?

The Ativan tablet comes in three strengths: 0.5 mg, 1 mg, and 2 mg. The liquid solution is available in two strengths: 2 milligrams per milliliter of solution (mg/mL) and 4 mg/mL.

What are the usual dosages of Ativan?

Your doctor will likely start you on a low dosage and adjust your dosage over time to reach the right amount for you. They’ll ultimately prescribe the lowest dose of Ativan that provides the desired effect. The normal dose of Ativan is different depending on the condition it’s used to treat.

The information below describes dosages that are commonly used or recommended. But be sure to take the dosage your doctor prescribes for you. They’ll determine the best dosage to fit your needs.

Dosage for sleep problems

If you have trouble sleeping because of stress or anxiety, Ativan may be used to help you sleep. For this use, you’ll take the tablet form of Ativan. The typical dosage is 2 mg to 4 mg taken daily before bed.

Dosage for certain seizures

Ativan is used to treat seizures that are caused by a condition called epilepsy. For this use, you’ll receive Ativan injections at a healthcare facility.

If you receive Ativan as an injection into a vein, the usual dosage is 4 mg given slowly (usually over about 2 minutes). If the seizure continues after 10 to 15 minutes, you may receive another 4-mg dose.

Dosage for anxiety

If you take Ativan for anxiety, you’ll be prescribed the tablet form of the drug.

Ativan’s dosage for anxiety ranges from 1 mg per day up to 10 mg per day. But the usual dosage is 2 mg or 3 mg taken daily. You’ll likely take this amount in separate doses. For example, if your daily dose is 3 mg, you may take 1 mg in the morning and 2 mg at bedtime.

Dosage for surgery

Ativan may be used to help you fall asleep before surgery and to help treat any anxiety you feel right before surgery. Your dosage will be based on your body weight.

If you receive Ativan as an injection into a vein, the usual dose is either 0.02 mg per pound of body weight or 2 mg total — whichever dose is smaller. In some cases, the highest dose you may receive before surgery is 4 mg.

If you receive Ativan as an injection into a muscle, the usual dose is 0.05 mg per kilogram (kg) of body weight. (One kg is about 2.2 pounds.) In some cases, the highest dose you could receive before surgery is 4 mg.

What’s the dosage of Ativan for children?

There isn’t an approved dose of Ativan for children. The drug isn’t approved for use in children.

Doctors sometimes prescribe Ativan off-label for children. (Off-label use is when a drug is prescribed to treat a condition it isn’t approved for.)

To learn more about Ativan’s off-label use in children, talk with your child’s doctor.

Is Ativan used long term?

No, Ativan isn’t typically used as a long-term treatment. It’s not recommended that you use Ativan for longer than 4 months in a row. Your doctor will prescribe the dosage and schedule that’s right for you.

Dosage adjustments

Your Ativan dose may need to be adjusted if you’re an older adult (age 65 years or older). You may also need a lower dose if you have liver or kidney problems. Talk with your doctor or pharmacist about the dose of Ativan that is best for you.

For certain uses, Ativan has a maximum recommended dosage per day. These uses include:

Prepping for surgery. To make you fall asleep before surgery, the maximum recommended dose of Ativan in one day is 4 mg. This dose is usually given as an injection into a vein.

Treating anxiety. To treat anxiety, the highest recommended dosage of Ativan in one day is 10 mg administered via tablet form. The 10-mg daily dose is divided into two or three separate doses taken throughout the day. For example, your dose might be 4 mg in the morning and 6 mg before bed.

If you have questions about your Ativan dosage, talk with your doctor or pharmacist.

Below are answers to some commonly asked questions about Ativan’s dosage.

What’s the Ativan dosage for anxiety attacks or alcohol withdrawal?

There isn’t a recommended dosage of Ativan for anxiety attacks or alcohol withdrawal because these are off-label uses of the drug. (Off-label use is when a drug is prescribed to treat a condition it isn’t approved for.)

Benzodiazepines, including Ativan, are currently being studied as a treatment for alcohol withdrawal. Doctors sometimes prescribe Ativan off-label for conditions such as alcohol withdrawal. If you’re prescribed Ativan for an off-label condition, your doctor will determine the dosage that’s right for you.

If you’re interested in taking Ativan off-label for anxiety attacks or alcohol withdrawal, talk with your doctor.

What’s the Ativan dosage for claustrophobia during an MRI or anxiety before a dental procedure?

Ativan is sometimes used for claustrophobia or anxiety during a magnetic resonance imaging (MRI) scan or anxiety during other medical procedures, such as dental work. This is an off-label use, so there isn’t a recommended dosage. If you’re prescribed Ativan for one of these purposes, your doctor will determine the dosage that’s right for you.

If you have questions about the off-label use of Ativan for claustrophobia or anxiety during medical procedures, talk with your doctor.

The dosage of Ativan you’re prescribed may depend on several factors. These include:

• the type and severity of the condition you’re using the drug to treat
• your age
• the form of Ativan you’re using
• other conditions you may have (see “Dosage adjustments” just above)
• your kidney and liver function

Ativan comes as a tablet that you swallow and as a liquid solution that’s given as an injection. The form of Ativan your doctor prescribes will depend on what it’s being used for.

You can take Ativan tablets with or without food. If you have trouble swallowing tablets, see this article for tips on how to take this form of medication. And for information on the expiration, storage, and disposal of Ativan, see this article.

If you’re prescribed the injection form of Ativan, your doctor will administer the injections into a vein or muscle. In most cases, injections are given as part of a surgical procedure or as an urgent treatment to stop a seizure.

Accessible drug containers and labels

If you find it hard to read the prescription label on your medication, tell your doctor or pharmacist. Some pharmacies provide medication labels that:

• have large print or use braille
• feature a code you can scan with a smartphone to change the text to audio

Your doctor or pharmacist may be able to recommend pharmacies that offer these accessibility features if your current pharmacy doesn’t.

If you have trouble opening medication bottles, let your pharmacist know. They may be able to supply Ativan in an easy-open container. They may also have tips to help make it simpler to open the drug’s container.

If you miss an Ativan dose, take it as soon as you remember. But if it’s almost time for your next dose, skip the missed dose and take the next one at its scheduled time. You should not take two doses of Ativan to make up for a missed dose. Doing so could raise your risk of side effects from the drug.

If you need help remembering to take your dose of Ativan on time, try using a medication reminder. This can include setting an alarm or downloading a reminder app on your phone.

Do not take more Ativan than your doctor prescribes, as this can lead to serious side effects.

Symptoms of overdose

Symptoms caused by an overdose of Ativan can include:

• trouble balancing
• coma
• drowsiness
• slowed reflexes
• confusion
• low blood pressure

In some cases, Ativan overdose can even be fatal. If you’re concerned about the risk of overdose with Ativan, talk with your doctor.

What to do in case you take too much Ativan

Call your doctor right away if you think you’ve taken too much Ativan. You can also call 800-222-1222 to reach the American Association of Poison Control Centers or use its online resource. But if you have severe symptoms, call 911 (or your local emergency number) immediately or go to the nearest emergency room.

Ativan is typically used short term. Long-term use of Ativan can lead to physical and mental dependence. With dependence, your body needs the drug to function like usual.

If your body becomes dependent on Ativan, you may have withdrawal symptoms when you stop taking it. (Withdrawal symptoms are side effects that can occur when you stop taking a drug that your body has become dependent on.)

Examples of withdrawal symptoms from stopping Ativan treatment may include:

• depression
• unusual movements, such as facial tics
• seizures
• fatigue (low energy)
• nausea, vomiting, and diarrhea
• hallucinations (seeing or hearing things that aren’t really there)
• sensitivity to light
• panic attack
• suicidal thoughts

In some cases, withdrawal symptoms from Ativan may last for up to 12 months. Examples include:

• weakness
• prickling feeling in your hands, arms, legs, or feet
• anxiety
• ringing in the ears
• twitching muscles
• insomnia (trouble sleeping)

Talk with your doctor about how to safely stop your Ativan treatment. They’ll likely have you reduce your dose slowly to help avoid withdrawal symptoms.

The sections above describe the usual dosages provided by the drugmaker. If your doctor recommends Ativan for you, they’ll prescribe the dosage that’s right for you.

Remember, you should not change your dosage of Ativan without your doctor’s recommendation. Only take Ativan exactly as prescribed. Talk with your doctor if you have questions or concerns about your current dosage.

Here are some examples of questions you may want to ask your doctor:

• How should I divide my daily dose if I take Ativan for anxiety?
• Does my dosage of Ativan need to change if I’m taking other drugs along with it?
• If I notice that I feel sleepy during the day, should I decrease my Ativan dose?
• What do I need to know about a dosage taper for Ativan?

If you take Ativan for anxiety, sign up for Healthline’s anxiety newsletter to get helpful tips and first-person stories.

Disclaimer: Healthline has made every effort to make certain that all information is factually correct, comprehensive, and up to date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or another healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.

Pharmaceutical Patent Strategies: Patent Greening

A.I. Orlova,
Master of the Moscow State Law University
named after O.E. Kutafina (Moscow State Law Academy),
lawyer LLC Legal Agency Right Bank
RF, Moscow

83-89

It is estimated that about 40-45 new drug molecules have been discovered in the last ten years. Whether this is too much or too little is debatable, but given the statistics, it has often been suggested in the pharmaceutical sector that the majority of patent applications claim secondary inventions. They can be protected by adding new claims to the claims using various effective and otherwise legitimate methods.

The issue of “evergreen” is one aspect of patenting that ultimately aims to increase the life cycle of legal protection for virtually the same invention. The technique of so-called greening is used mainly by pharmaceutical companies to develop tightly stocked patent portfolios around the most profitable drug molecules. The landscaping process itself is carried out by obtaining protection for various claims (aspects) of the invention, conditionally meeting the criteria for patentability, in addition to the protection of the main invention (more on this below). Ultimately, this process leads to an extension of the patent term for virtually the same drug for another 20 years, and thus allows pharmaceutical companies to maintain a monopoly in the market for innovative drugs.

In accordance with paragraph 1 of Art. 27 of the Agreement on Trade-Related Aspects of Intellectual Property Rights (hereinafter referred to as TRIPS), patents are granted for any invention, regardless of whether they are a product or a method in all fields of technology, provided that they are novel, contain an inventive step and are industrially applicable. In addition, patents are granted and the rights based on a patent can be exercised regardless of where the invention was created, the field of technology, and whether the products are imported or produced locally.

The TRIPS Agreement provides international protection for the intellectual property of pharmaceutical companies. The member countries of the Agreement commit to adhere to strict rules that respect minimum standards for the granting of patents and the implementation of their protection, which in turn indirectly increases the growth of the pharmaceutical industry, therefore – contributes to a wider range of inventions and the availability of medicines.

However, problems still arise with regard to international trade legislation concerning public health protection, and developing and underdeveloped countries face pressure from pharmaceutical companies to access export markets, which threatens public health.

Patenting and pharmacological research costs

Pharmaceutical companies invest huge amounts of time and money in research and development of drugs for the benefit of mankind. It should be noted that the development of a pharmaceutical drug goes through many stages before the manufacturer receives permission to bring the drug to the market, which inevitably leads to uncertainty about the possible profit, which can be either zero or multi-million dollar. Maximizing confidence that a manufacturer that has invested in research can obtain, secure, protect and legally exercise the rights to its intellectual property is essential to sustaining innovation for the benefit of the public interest and public health. The absence of effective mechanisms for the protection of intellectual property rights at any stage of the innovation cycle inevitably leads to a decrease in the interest of innovative pharmaceutical companies in further developments.

Pharmaceutical companies are screening a huge number of molecules, and of the thousands of potential drugs selected, only 4-5 are going through clinical trials, of which only one will be approved and released. It takes an average of $800 million to develop and test a new drug. In the case of pharmaceutical companies, a monopoly on the results of their research and development is an opportunity to obtain funds that will pay off huge investments. The costs of research conducted to select a molecule and move to the stage of clinical trials are reimbursed through the appropriate pricing mechanisms for patented drugs. Giving an inventor market exclusivity through patent protection can incentivize the upfront investment of resources needed to develop a product. In addition, investment by innovators in the development of molecules that have already entered the market also stimulates investment in further research, development and improvement of existing products.

Innovative drugs or generics?

A patent is a form of insurance for innovative pharmaceutical companies. Prescription drugs are known to be at the greatest risk to manufacturers.

Prescription products are classified into therapeutic categories. Although patents formally prohibit competitors from withdrawing analog drugs before the patent expires, patents do not prevent the manufacture and sale of different drugs for the same disease in a given therapeutic category. One such category is COX-2 inhibitors, which are commonly used in the treatment of arthritis. There are various types of prescription and over-the-counter drugs available on the market to treat this condition. Non-steroidal anti-inflammatory drugs (NSAIDs), which fall under the action of COX-2 inhibitors, are used to treat pain and inflammation associated with arthritis. COX-2 inhibitors are relatively recent and have become of paramount importance due to their ability to reduce the side effects of gastric bleeding and ulcers compared to the prescription of more traditional NSAIDs. However, some of the COX-2 drugs cause serious side effects that affect the heart. In addition, COX-2 products are significantly more expensive than prescription NSAIDs. The cost comparison factor is also taken into account when prescribing a drug to a patient.

Every patent for an innovative drug that expires requires a huge investment for innovators, generics and consumers alike. The Federal Antimonopoly Service monitors patent disputes between innovators and generic companies and is particularly concerned about possible anti-competitive practices used by innovative pharmaceutical companies. Some of these anti-competitive practices that help green forever include brand migration, agreements between innovators and generics, and agreements between generics, which are discussed below.

Pharmaceutical patent greening strategies

As noted earlier, innovative companies seek to extend the validity of their patents by registering new invention solutions, such as: treatments, mechanism of action, isomeric forms, delivery profiles, dosing regimen and range, combinations, screening methods, biological targets and application area. As patent life increases, innovators maximize revenue from their evergreen products, effectively eliminating any early-stage competition.

In the context of landscaping, the decision of the Supreme Court of India to deny the Swiss pharmaceutical company Novartis a patent for a new version of the anti-cancer drug Gleevec (the active ingredient is imatinib mesylate) is interesting. According to Novartis, the patented drug is more readily absorbed into the bloodstream than previously patented drugs, and given that it is used to fight leukemia, this is enough to provide patent protection. After six years of litigation, the Court found that, according to patent law, a new version of an old drug must demonstrate improved efficacy in order to be granted patent protection [1]. Interestingly, just a month before this event, the Supreme Court of India granted a compulsory license for the cancer drug Bayer Nexavar for the first time, reducing the price from over $5,500 per month to $175 [2].

It is important to note that at the time of these decisions, India was the first country in the world to take this step. Today, this practice is gaining ground: in particular, on January 25, 2019, the Moscow Arbitration Court satisfied the claim of Nativa LLC for the issuance of a compulsory license to use the patent for the drug with INN sunitinib, owned by Sugen LLC and Pharmacia & Upjohn Company. Note that since 1995, more than a hundred attempts have been made to obtain compulsory licenses [3]. Regarding antimonopoly regulation, the FAS RF takes an active position on the issue of a ban on landscaping patents, introducing bills and draft by-laws for consideration.

Patent greening strategies commonly used in the pharmaceutical industry include the following.

•

Excess expansion and creation of new generation drugs patented as modern drugs (brand migration) .

Various items (aspects) of innovative drugs include delivery profiles, production methods, chemical intermediates, formulations, dosing regimen, isomeric forms, mechanism of action and treatment method, etc. Often innovator firms use one of these aspects to obtain an additional patent shortly before the expiration of the main patent. Therefore, if a branded pharmaceutical company formulates a new molecule for the treatment of a certain disease, the company is entitled to obtain patent protection for various aspects of the parent drug, these additional patents covering different aspects of the same drug will add a term to the total term of the original patent and limit running generic.

For example, when the patent for Prilosec was nearing expiration, AstraZeneca, to maintain its monopoly on Prilosec, released Nexium, which was the same drug with minor changes in design and color [4].

•

Exclusive partnerships with generic market participants prior to patent expiration, significantly increasing brand value and earning product royalties in the interim. .

This antitrust practice is widely used by innovative companies that try to keep the corresponding generic drug out of the market. For example, innovative companies negotiate with generic manufacturers to delay the entry of specific generics into the market.

A prime example is tamoxifen, marketed by the pharmaceutical company Astra Zeneca under the trade name Novaldex. Astra Zeneca and generic maker Barr have reached an agreement whereby Astra Zeneca has committed to a one-time payment of $66.4 million to delay the release of a generic drug for up to 10 years. In addition, in addition, Barr was able to sell the drug tamoxifen created by Astra Zeneca under the Barr brand.

Another example is the agreement between AstraZeneca and the Indian generics manufacturer Torrent Pharmaceuticals, under which Torrent assumed responsibility for the production and supply of generics for AstraZeneca’s emerging markets [5].

The opposite of anticompetitive agreements is an agreement between manufacturers of generic drugs directly. One such example is the activities of Mylan Laboratories Inc. in an attempt to monopolize, namely the conclusion of agreements related to the supply of key ingredients for two widely prescribed drugs for anxiety – lorazepam and clorazepate. For example, Mylan Laboratories Inc. effectively restricted trade by signing exclusive license agreements for the supply of raw materials with Profarmaco SRL, the largest supplier of raw materials for the drugs lorazepam and clorazepate.

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The practice of defensive pricing strategies where innovative companies lower the price of a product and bring it in line with the prices of other market players for healthy competition .

Following this practice, innovators immediately after the expiration of the patent begin selling a cheaper version of the branded drug, thereby reducing the price of generic analogues, which leaves competitors far behind. So, as a result, prices for generics can fall by 40% or more within two years [6].

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Establishment of subsidiaries by relevant innovators before competitors emerge .

Pharmaceutical giants have recently shown increasing interest in creating generic subsidiaries and entering into partnerships with major generic manufacturers before competition from generic players intensifies. Over the past decade, Big Pharma companies have acquired small, one-stop units to expand their business model. For example, Novartis established Sandoz as a subsidiary of its generics business, and Novartis’ generic profits rose to $7.5 billion (until 2009).G.). Novartis acquired the oncology generics business, which further increased their profits [7].

Provisions in US, EU, RF and other laws to prevent permanent greening

US policy

In order to strike a balance between the interests of generic and innovative drug manufacturers, the Hatch-Waxman Act was passed in 1984 in the United States. This balance was proposed to be found through certain provisions that are useful both for the generic manufacturer and for innovative companies. Thus, the said law contains a provision on the remuneration of the manufacturer of generics, which is the first to challenge the patent of the innovator.

The first generic applicant, if successful in challenging the patent, receives a 180-day exclusion period, which gives the generic manufacturer the opportunity to sell its products exclusively. The 180-day exclusion period is in recognition of the public interest in encouraging generic manufacturers to produce generic versions of innovative drugs and to block the unjustified monopolies enjoyed by green patents.

The Hatch-Waxman Act introduced a new procedure whereby a generic drug manufacturer can file an ANDA (Abbreviated New Drug Application) with the U.S. Food and Drug Administration (and Cosmetics) ).

The underlying fact behind this scheme is that if an innovative drug is already approved, a generic version would need to demonstrate an identical biological effect to be approved and put on the market, rather than repeat clinical trials over and over again. To balance the interests of innovators, the law requires a generic applicant to choose one of four certificates regarding the patent status of a competing generic:

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item I – medicine not patented;

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point II – the term of the drug patent has expired;

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item III – patent expires by the time generics are on the market;

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point IV – the patent will not be infringed or the patent will be invalid [8].

EU policy

There are not many laws in the European Union to prevent permanent greening, however, it should be noted that permanent greening in the European Union is considered an abuse of dominance and is regulated under Art. 102 of the Treaty on the Functioning of the European Union (TFEU). Due to the fact that a patent is an exclusive right granted to the patent owner, and the patent owner has the right to use the patent exclusively, the actions of the right holder may not always be considered an abuse of dominant position. Evergreen appears to be forced into the scope of Art. 102, therefore this article needs a narrow and clear definition to be consistent with the concept of evergreen, since the existing definition is too broad and the use of this provision seems impossible. A similar problem is seen in Russian legislation.

Russian policy

In 2018, the Ministry of Economic Development submitted a draft amendment to the rules for state registration of inventions, directed against evergreen patents. The changes concern, first of all, the registration of new medicines. According to the draft law, it is proposed to limit the use of a number of features in the description of the invention. It is established that when evaluating novelty or inventive step, information that is not directly related to the composition will not be taken into account. Such information includes, in particular: the conditions and modes of use in any process and method, the technical result that manifests itself during manufacture or use, etc. When characterizing a medicinal product, it is not allowed to use signs related to the method of treating or preventing a disease, for example: indication doses, conditions or modes of use, drugs derived from it [9]. This approach is expected to avoid double patenting. Similar initiatives have been made before. Thus, in the draft “Development of competition in the healthcare sector” presented in May 2016, one of the necessary measures was “the establishment of restrictions on the issuance of patents for the discovery of any new property or new application of an already known active substance of a drug” [10].

As of today, there are no provisions on the prohibition of the practice of gardening in the legislation of the Russian Federation. Moreover, a number of experts express doubts about the introduction into the legislation of norms restricting the patenting of secondary inventions. So, according to Vorozhevich A.S., the establishment of additional criteria for the patentability of secondary inventions does not significantly affect the practice of patenting [11]. Another argument expressed by Vorozhevich A.S. is that already now in the domestic legislation there are serious disincentives for the import of medicines into Russia. This will inevitably entail the refusal of foreign pharmaceutical manufacturers to release new drugs on the Russian market.

Indian policy

In India, there has been increased lobbying against the inclusion of data exclusivity provisions for the pharmaceutical and agrochemical sectors, as this is considered to be in the public interest. Moreover, it is pointed out that the inclusion of such provisions could have a huge impact on the generic pharmaceutical industry and could delay the entry of cheaper drugs to the market. The inclusion of a data exclusivity clause in the Indian intellectual property regime would also entail the concept of patent greening.

Under the provisions of Indian law, new forms of already known substances are not patentable unless they are proven to increase the known efficacy of the previously known substance. The purpose of introducing such a restriction was to limit the practice of perpetual gardening. Section 3(d) limits the patentability of certain newer forms of older substances if they do not meet the requirement for increased performance criteria. Thus, the law states that “the discovery of a new form of a known substance that does not increase the known efficacy of that substance, or the discovery of any new property or new use of a known substance, or the use of a known method, if such a method does not lead to to a new product or does not use at least one new reagent” [12].

Thus, the law sets higher patentability standards for new forms of already known substances. Moreover, such a provision has already proven to be an effective provision in the verification of evergreen patents.

Conclusion

Because drug development involves many risks, and every successful drug molecule is backed by decades of extensive clinical research and development, patent life begins long before drug development. Most countries provide 20-year patent protection for innovative drugs. Much of this time is lost in the course of applying for and getting approval to go to market, so it is natural for any innovative firm to resort to practices that increase the duration of monopolization, in particular, the practice of patent gardening in order to recoup the huge costs that they incur on R&D. However, over time, these practices have become too aggressive.

In developed countries such as the United States, the European Union and the Russian Federation, patent laws are too lenient to have a positive effect on reducing the number of evergreen patents. India is doing the opposite. As shown in the Novartis case, India has given a clear indication that the state will not risk public health and public health by allowing drug patents to be greened forever. The Novartis decision sent a powerful signal to the world and to innovative firms that India will only grant an extended market monopoly to pharmaceutical companies if it can be shown that the drug is indeed innovative and that the effectiveness is greatly improved.

Our country has recently chosen a similar path. Although the mechanisms are not yet in place, and the actions of public authorities are often criticized, in general, the approach aimed at eliminating green patents seems to be correct. However, in our opinion, the improvement of legislation in one country, without the application of appropriate measures by countries around the world, seems to be ineffective and, moreover, disastrous in terms of public health and healthcare of a country that has allowed itself to reduce the level of patent protection. Thus, a direct relationship has been proven between the degree of patent protection in the state and the speed of entry of new drugs into its market: if strong patent rights accelerate the import of relevant drugs, then weak patent rights hinder the import and increase the availability of drugs.

Patent gardening appears to encourage unfair competition and related abuses. Stronger intellectual property controls around the world could eradicate this practice, which is widely followed by pioneering companies, in order to create a checkpoint for generic companies that seek to provide safe and effective medicines to the masses at cost-effective prices. Decisions in landmark cases can help to understand the complex issue of evergreen patents. It is important to find a balance between promoting the innovation activities of large companies and at the same time protecting the efforts made by generic companies, so that cost-effective products appear on the market in an even balance, thereby benefiting the masses.

References

[1] Collier R. Drug patents: the evergreening problem. CMAJ. 2013; 185(9):E385-E386. doi:10.1503/cmaj. P. 109-166.

[2] Patent wars: has India taken on Big Pharma and won? // The Guardian URL: https://www.theguardian.com/sustainable-business/patent-wars-india-takes-on-big-pharma?CMP=share_btn_tw (Accessed 23 July 2019).

[3] Kyung-Bok Son, Chang-yup Kim, Tae-Jin Lee. Understanding of for whom, under what conditions and how the compulsory licensing of pharmaceuticals works in Brazil and Thailand: A realist synthesis. // Global Public Health 14:1. Taylor & Francis, 2019. P. 122-134.

[4] Shuchi M. Strategies for drug patent Ever-greening in the Pharmaceutical industry. Int J Pharmaceut Sci Business Manag. 2015.3:11-24.

[5] Authorized Generic Drugs: Short-Term Effects and Long-Term Impact. Federal Trade Commission (2011) Federal Trade Commission.

[6] Anti-Trust: Pharmaceuticals (2017) European Commission.

[7] Authorized Generic Drugs: Short-Term Effects and Long-Term Impact. Federal Trade Commission (2011) Federal Trade Commission.

[8] Gongola J.A. (2003) Prescriptions for change: The Hatch-Waxman Act and new legislation to increase the availability of generic drugs to consumers. Indiana Law Review 36: 787-825.

[9] Draft “On Amendments to the Rules for Compiling, Submitting and Reviewing Documents Constituting the Basis for Legally Significant Actions for the State Registration of Inventions, and Their Forms and Requirements for the Documents of an Application for a Patent for an Invention, approved by order of the Ministry of Economic Development of the Russian Federation dated May 25, 2016″ No. 316.

[10] Exclusive out of time. In Russia, they may limit the patent protection of medicines // RG. Dec 16, 2015

[11] Vorozhevich A.S. Secondary drug patents: should they be restricted? // Law.

[12] Rathod SK (2010) Ever-greening: A status check in selected countries. J Generic Med 7: 227-242.

Selma Blair: How an actress lives with multiple sclerosis

On Thursday, August 16, 2018 at 10:00 pm, Selma Blair lay in an MRI machine, her body twitching uncontrollably. She tried not to pay attention, she had a backache in her neck for a long time, then her head would spin, then her leg would lose sensation. Plus anxiety and depression. A few years ago, Selma suddenly became very tired – so that every morning, taking her son to school, she fell like a bag back into bed. I had to tell the agent not to offer a job far from Los Angeles, there was no energy for business trips. But Blair is a single mom with a mortgage. So in 2017, she got out of bed and confirmed filming in Atlanta for After and in Vancouver for the Netflix series Another Life.

By that time, the woman had already come to terms with the fact that doctors attributed her problems to depression, hormones, or the fact that she was an actress and inclined to make a drama out of any nonsense. And I went to the clinic for the only thing that relieved the pain in my neck – a simple injection of a steroid. But the new doctor immediately sent her for an MRI. Selma, in hospital pajamas and fluffy socks, was shoved head first into a coffin-sized cell. Compared to the feeling that the body is slowly becoming a stranger, this was nonsense. She was offered to listen to some music – she chose Pink, Just Give Me a Reason, and naturally shed tears while the tomograph scanned her brain. He found twenty lesions. An hour later, a neurologist will say that this most likely means multiple sclerosis – an incurable autoimmune disease in which the central nervous system loses communication with the body.

The first feeling was relief. It’s good that the muck that arranges this chaos in the body has a name. Good thing it’s not amyotrophic lateral sclerosis like Stephen Hawking. Then Selma Blair became afraid of the unknown. How will the body react to treatment attempts? Can she ever regain control of her physical being? There were ten more minutes of tears. Then there was work to be done.

“A walking stick, I think it could be a cool accessory.”

Noreen Halpern, executive producer of Another Life, told me that Blair’s manager immediately informed her of his client’s diagnosis. “That’s exactly what I wrote:“ Selma is worried that you will refuse to cast her in the series. What a wildness! We really wanted to shoot it. My heart sank at the thought of her battling the unknown, confident that we had no intention of stepping into her position. We gave the answer: “The project will take place as agreed.” Selma finished work in Atlanta and immediately flew to Vancouver to shoot a series about astronauts. Selma is a professional, Halpern reminded me. “No one knew about the diagnosis until she herself decided to make this information public. ”

In mid-October 2018, the actress wrote a long post on Instagram. That she has multiple sclerosis. That she is grateful to the Other Life team for their support. “I didn’t do it to brag about a difficult diagnosis. For some reason, it didn’t occur to me that the post would scatter over the Internet, ”Selma justified herself in front of me. – I felt embarrassed. And restless. What if no one else offers a job?

I have to say that her black humor is just great: “I was immediately contacted by a bunch of people who thought I was going to collapse dead in the very near future.” American comedian Amy Schumer called, her dad also has multiple sclerosis. And Marc Jacobs, an old friend who once named a bag after Selma. Kris Jenner sent flowers that, Blair laughs, “cost more than my mortgage.” Three months later, her health deteriorated sharply, and the actress stopped being ironic: “To be honest, I didn’t think it would come to this.”

Blair and I sit down to dinner in a corner of a dark restaurant in Soho.