Laboratories Div Pfizer Inc

PAXLOVID-nirmatrelvirおよびritonavirPfizer 

Laboratories Div Pfizer Inc

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医療提供者のためのファクトシート:PAXLOVID™の緊急使用許可
緊急使用許可(EUA)のハイライトこれらのEUAのハイライトには、EUAでPAXLOVID™を使用するために必要なすべての情報が含まれているわけではありません。PAXLOVIDの医療提供者向けの完全なファクトシートを参照してください。
PAXLOVID(ニルマトレルビル錠;リトナビル錠)、経口使用のために共同パッケージされた元のEUA承認日:12/2021
————– EUA FOR PAXLOVID ———- ——–米国食品医薬品局は、未承認のPAXLOVIDの緊急使用のためにEUAを発行しました。これには、SARS-CoV-2メインプロテアーゼ(Mpro:3CLproまたはnsp5プロテアーゼとも呼ばれます)阻害剤であるニルマトレルビルと、HIV- 1プロテアーゼ阻害剤およびCYP3A阻害剤、成人および小児患者(12歳以上体重40 kg以上)の軽度から中等度のコロナウイルス病2019(COVID-19)の治療に使用され、直接的な重症急性呼吸器の陽性結果が得られます症候群コロナウイルス2(SARS-CoV-2)ウイルス検査、および入院や死亡を含む重症COVID-19への進行のリスクが高い人。
許可された使用の制限PAXLOVIDは、重症または重篤なCOVID-19のために入院を必要とする患者の治療開始を許可されていません。PAXLOVIDは、COVID-19の予防のための曝露前または曝露後の予防には認可されていません。PAXLOVIDは、連続5日を超えて使用することは許可されていません。PAXLOVIDは、PAXLOVIDが属する治療クラスの薬(すなわち、抗感染薬)を処方するために州法の下で認可または認可された医師、上級診療登録看護師、および医師助手によってのみ、個々の患者に処方することができます。
PAXLOVIDは、COVID-19の治療薬としての使用を含め、いかなる使用も承認されていません。(1
PAXLOVIDは、法第564条(b)(1)、21USC§360bbb-3(b)(1)に基づくPAXLOVIDの緊急使用の許可を正当化する状況が存在するという宣言の期間中のみ許可されます。 、承認がより早く終了または取り消されない限り。
COVID-19のパンデミック中の薬物の緊急使用の正当性、利用可能な代替案に関する情報、およびCOVID-19に関する追加情報については、医療提供者向けの完全なファクトシートを参照してください。—–投与量と投与—— PAXLOVIDは、リトナビル錠と一緒にパッケージされたニルマトレルビル錠です。(2.1)ニルマトレルビルはリトナビルと同時投与する必要があります。(2.1)COVID-19の診断後、症状の発現から5日以内に、できるだけ早くPAXLOVID治療を開始してください。(2.1)食物の有無にかかわらず経口投与します。(2.1)投与量:300mgのニルマトレルビル(2つの150mgの錠剤)と100mgのリトナビル(1つの100mgの錠剤)、3つの錠剤すべてを1日2回5日間一緒に服用します。(2.1
中等度の腎機能障害( eGFR≥30〜<60 mL / min)の減量:150 mgのニルマトレルビル(1つの150 mg錠)と100 mgのリトナビル(1つの100 mg錠)、両方の錠剤を1日2回5日間一緒に服用します。(2.2)PAXLOVIDは、重度の腎機能障害(eGFR <30 mL / min)の患者には推奨されません。(2.28.6)PAXLOVIDは、重度の肝機能障害(チャイルドピュークラスC)の患者には推奨されません。(2.38.7—–剤形と強度—–錠剤:ニルマトレルビル150 mg(3)錠剤:リトナビル100 mg(3———–禁忌————-有効成分(ニルマトレルビルまたはリトナビル)またはその他の成分に対する臨床的に重要な過敏反応の病歴。(4)クリアランスをCYP3Aに大きく依存し、濃度の上昇が深刻なおよび/または生命を脅かす反応に関連する薬物との同時投与。(47.3)強力なCYP3A誘導剤との同時投与では、ニルマトレルビルまたはリトナビルの血漿濃度が大幅に低下し、ウイルス学的反応の喪失および耐性の可能性が失われる可能性があります。(4—–警告と注意——PAXLOVIDと他の特定の薬物を併用すると、潜在的に重大な薬物相互作用が生じる可能性があります。潜在的な薬物相互作用については、治療前および治療中に完全な処方情報を参照してください。(5.17)肝毒性:リトナビルを投与されている患者では、肝トランスアミナーゼの上昇、臨床的肝炎、黄疸が発生しています。(5.2)HIV-1の薬剤耐性:PAXLOVIDを使用すると、HIV-1感染が制御されていない、または診断されていない個人において、HIV-1がHIVプロテアーゼ阻害剤に対する耐性を発現するリスクが生じる可能性があります。(5.3————有害反応———–有害事象(発生率≥1%および≥5被験者差)は、味覚障害、下痢、高血圧、および筋肉痛でした。(6.1
あなたまたはあなたの被指名人は、PAXLOVIDに関連する可能性のあるすべての重篤な有害事象または投薬エラーを(1)FDAフォーム3500をオンラインで提出することによって、(2)このフォームをダウンロードしてから郵便またはファックスで提出することによって、または(3)連絡することによって報告しなければなりません。このフォームを要求するには、FDA(1-800-FDA-1088)。このフォームのコピーをファイザー社にファックス番号1-866-635-8337で提供してください。(6.4
————-薬物相互作用————-PAXLOVIDの同時投与は、他の薬剤の血漿中濃度を変化させる可能性があり、他の薬剤はPAXLOVIDの血漿中濃度を変化させる可能性があります。PAXLOVID療法の前および最中の薬物相互作用の可能性を検討し、PAXLOVID療法中の併用薬を確認してください。(2.445.1712.3
患者、保護者、介護者とファクトシートを参照してください。
目次*
   1緊急使用許可 2投与量と投与 2.1PAXLOVIDの緊急使用のための投与量 2.2腎機能障害のある患者における重要な投薬情報 2.3肝機能障害のある患者での使用 2.4PAXLOVIDとの重要な薬物相互作用 3剤形と強み 4禁忌 5警告と注意事項 5.1薬物相互作用による重篤な副作用のリスク 5.2肝毒性 5.3HIV-1耐性発症のリスク 6副作用 6.1臨床試験からの副作用 6.4重篤な有害事象および投薬エラーについて必要な報告 7薬物相互作用 7.1PAXLOVIDが他の薬剤に影響を与える可能性 7.2他の薬剤がPAXLOVIDに影響を与える可能性 7.3確立されたおよびその他の潜在的に重要な薬物相互作用 8特定の集団での使用   8.1妊娠 8.2授乳 8.3生殖能力のある雌雄 8.4小児への使用 8.5老年医学的使用 8.6腎機能障害 8.7肝機能障害 10過剰摂取 11説明 12臨床薬理学 12.1作用機序 12.3薬物動態 12.4微生物学 13非臨床毒性学 13.1発がん、突然変異誘発、出産性の障害 13.2動物毒性学および/または薬理学 14臨床試験 14.1重度のCOVID-19感染症に進行するリスクが高い被験者における有効性 16供給/保管および取り扱い方法 17患者カウンセリング情報 18メーカー情報   * EUAから省略されたセクションまたはサブセクションはリストされていません。

医療提供者のための完全なファクトシート

1緊急使用許可

米国食品医薬品局(FDA)は、成人および小児患者における軽度から中等度のコロナウイルス病2019(COVID-19)の治療のための未承認製品PAXLOVIDの緊急使用に関する緊急使用許可(EUA)を発行しました( 12歳以上で体重が40kg以上)、直接重症急性呼吸器症候群コロナウイルス2(SARS-CoV-2)ウイルス検査の陽性結果があり 、入院を含む重症COVID-19への進行のリスクが高い1または死。


1

重度のCOVID-19に進行するリスクの増加に関連する病状と要因については、米国疾病予防管理センター(CDC)のWebサイトを参照してください:https://www.cdc.gov/coronavirus/2019-ncov/need- extra-precautions /people-with-medical-conditions.html。医療提供者は、個々の患者のベネフィットリスクを考慮する必要があります。

許可された使用の制限

  • PAXLOVIDは、重症または重篤なCOVID-19のために入院を必要とする患者の治療開始を許可されていません[投与量と投与(2.1)を参照]2
  • PAXLOVIDは、COVID-19の予防のための曝露前または曝露後の予防としての使用は許可されていません。
  • PAXLOVIDは、連続5日を超えて使用することは許可されていません。

PAXLOVIDは、PAXLOVIDが属する治療クラスの薬(すなわち、抗感染薬)を処方するために州法の下で認可または認可された医師、上級診療登録看護師、および医師助手によってのみ、個々の患者に処方することができます。

PAXLOVIDは、COVID-19の治療に使用することを含め、いかなる使用も承認されていません。

PAXLOVIDは、法第564条(b)(1)、21USC§360bbb-3(b)(1)に基づくPAXLOVIDの緊急使用の許可を正当化する状況が存在するという宣言の期間中のみ許可されます。承認はより早く終了または取り消されます。


2

PAXLOVIDによる治療を開始した後、重度または重大なCOVID-19のために入院が必要な患者は、医療提供者の裁量により、5日間の治療コース全体を完了することができます。

COVID-19パンデミック中の薬物の緊急使用の正当化

現在、新しいコロナウイルスであるSARS-CoV-2によって引き起こされるCOVID-19の発生があります。保健福祉長官(HHS)は、次のように宣言しています。

  • COVID-19に関連する公衆衛生上の緊急事態は、2020年1月27日から存在しています。
  • COVID-19パンデミック(2020年3月27日宣言)中の薬物および生物学的製品の緊急使用の承認を正当化する状況が存在します。

EUAは、米国食品医薬品局による、特定の状況下での未承認の製品の緊急使用または承認済みの製品(つまり、医薬品、生物製剤、またはデバイス)の未承認の使用に関する認可です。 HHSの長官が、国の安全または海外に住む米国市民の健康と安全に影響を及ぼし、生物剤またはそのような薬剤に起因する可能性のある疾患または状態を伴う公衆衛生緊急事態があると宣言した場合(s)。EUAを発行するための基準は次のとおりです。

  • 生物学的因子は、深刻なまたは生命を脅かす病気または状態を引き起こす可能性があります。
  • 利用可能な科学的証拠の全体(利用可能な場合は、適切で十分に管理された臨床試験からのデータを含む)に基づいて、次のことを信じるのは合理的です。
    • 製品は、深刻なまたは生命を脅かす病気または状態の診断、治療、または予防に効果的である可能性があります。と
    • 製品の既知の潜在的な利点は、そのような病気や状態の診断、予防、または治療に使用される場合、生物剤によってもたらされる重大な脅威を考慮して、製品の既知の潜在的なリスクを上回ります。
  • 深刻な、または生命を脅かす病気や状態を診断、予防、または治療するための、製品に代わる適切で承認された利用可能な代替品はありません。

EUA許可使用のために利用可能な代替案に関する情報

成人および小児患者(12歳以上で体重40kg以上)の軽度から中等度のCOVID-19の治療にPAXLOVIDに代わる承認された代替品はなく、直接SARS-CoV-2ウイルス検査の結果が陽性です。入院や死亡など、重症COVID-19に進行するリスクが高い人。

他の治療法は現在、PAXLOVIDと同じ使用が許可されています。COVID-19の治療または予防が許可されているすべての製品の詳細については、https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-を参照してください。使用許可。

COVID-19でのPAXLOVIDの使用をテストしている臨床研究については、www.clinicaltrials.govを参照してください。

2投与量と投与

2.1PAXLOVIDの緊急使用のための投与量

PAXLOVIDは、リトナビル錠と一緒にパッケージされたニルマトレルビル錠です。

ニルマトレルビルはリトナビルと同時投与する必要があります。ニルマトレルビルをリトナビルと正しく同時投与しないと、望ましい治療効果を達成するには不十分なニルマトレルビルの血漿レベルが生じる可能性があります。

PAXLOVIDの投与量は、300 mgのニルマトレルビル(2つの150 mg錠)と100 mgのリトナビル(1つの100 mg錠)で、3つの錠剤すべてを1日2回5日間経口投与します。処方箋は、PAXLOVID内の各有効成分の数値用量を指定する必要があります。ウイルスクリアランスを最大化し、SARS-CoV-2の感染を最小化するには、5日間の治療コース全体を完了し、公衆衛生の推奨事項に従って隔離を継続することが重要です。

PAXLOVIDの5日間の治療コースは、COVID-19の診断が下された後、症状が現れてから5日以内にできるだけ早く開始する必要があります。PAXLOVIDによる治療を開始した後、患者が重症または重大なCOVID-19のために入院を必要とする場合、患者は医療提供者の裁量により5日間の治療コース全体を完了する必要があります。

患者が通常服用してから8時間以内にPAXLOVIDの服用を逃した場合、患者はできるだけ早く服用し、通常の服用スケジュールを再開する必要があります。飲み忘れた場合は、1回分を8時間以上飲まないでください。忘れた分は飲まないでください。次の服用時間に1回分を飲んでください。患者は、逃した用量を補うために用量を2倍にすべきではありません。

PAXLOVID(ニルマトレルビルとリトナビルの両方の錠剤)は、食物の有無にかかわらず摂取できます[臨床薬理学(12.3)を参照]。錠剤は丸ごと飲み込み、噛んだり、壊したり、つぶしたりしないでください。

2.2腎機能障害のある患者における重要な投薬情報

軽度の腎機能障害(eGFR≥60〜 <90 mL / min)の患者では、投与量の調整は必要ありません。中等度の腎機能障害(eGFR≥30〜 <60 mL / min)の患者では、PAXLOVIDの投与量は150mgのニルマトレルビルと100mgのリトナビルを1日2回5日間投与します。処方箋は、PAXLOVID内の各有効成分の数値用量を指定する必要があります。医療提供者は、腎投与の指示について患者にカウンセリングする必要があります[患者カウンセリング情報(17)を参照]。

PAXLOVIDは、より多くのデータが利用可能になるまで、重度の腎機能障害(eGFR <30 mL / min)の患者には推奨されません。重度の腎機能障害のある患者に適切な投与量は決定されていません[特定の集団での使用(8.6)および臨床薬理学(12.3)を参照]。

2.3肝機能障害のある患者での使用

軽度(チャイルドピュークラスA)または中等度(チャイルドピュークラスB)の肝機能障害のある患者では、投与量の調整は必要ありません。重度の肝機能障害のある被験者(チャイルドピュークラスC)でのニルマトレルビルまたはリトナビルの使用に関する薬物動態または安全性のデータはありません。したがって、PAXLOVIDは、重度の肝機能障害のある患者への使用は推奨されていません[特定の集団での使用(8.7)を参照]

2.4PAXLOVIDとの重要な薬物相互作用

リトナビルまたはコビシスタットを含む他の製品と同時投与する場合、投与量の調整は必要ありません。

リトナビルまたはコビシスタットを含むHIVまたはHCVレジメンの患者は、指示に従って治療を継続する必要があります。

PAXLOVIDとの重要な薬物相互作用については、ファクトシートの他のセクションを参照してください。PAXLOVID療法の前および最中の薬物相互作用の可能性を検討し、PAXLOVID療法中の併用薬を確認します[禁忌(4)警告および注意事項(5.1)、および薬物相互作用(7)を参照]。

3剤形と強み

PAXLOVIDは、リトナビル錠と一緒にパッケージされたニルマトレルビル錠です。

  • ニルマトレルビルは、片面に「PFE」、もう片面に「3CL」がデボス加工された、楕円形のピンク色の即時放出型フィルムコーティング錠として提供されます。各錠剤には150mgのニルマトレルビルが含まれています。
  • リトナビルは、「a」のロゴとコードNKがデボス加工された白いフィルムコーティングされた卵形錠剤として提供されます。各錠剤には100mgのリトナビルが含まれています。

4禁忌

PAXLOVIDは、その有効成分(ニルマトレルビルまたはリトナビル)または製品の他の成分に対する臨床的に重大な過敏反応[例えば、中毒性表皮壊死症(TEN)またはスティーブンス-ジョンソン症候群]の病歴のある患者には禁忌です。

PAXLOVIDは、クリアランスをCYP3Aに大きく依存し、濃度の上昇が深刻なおよび/または生命を脅かす反応に関連する薬物と禁忌です[薬物相互作用(7.3)を参照]

  • アルファ1-アドレナリン受容体拮抗薬:アルフゾシン
  • 鎮痛薬:ペチジン、ピロキシカム、プロポキシフェン
  • 狭心症治療薬:ラノラジン
  • 抗不整脈薬:アミオダロン、ドロネダロン、フレカイニド、プロパフェノン、キニジン
  • 痛風防止:コルヒチン
  • 抗精神病薬:ルラシドン、ピモジド、クロザピン
  • 麦角誘導体:ジヒドロエルゴタミン、エルゴタミン、メチルエルゴノビン
  • HMG-CoAレダクターゼ阻害剤:ロバスタチン、シンバスタチン
  • PDE5阻害剤:シルデナフィル(レバティオ®)、肺動脈高血圧症(PAH)のために使用
  • 鎮静剤/催眠剤:トリアゾラム、経口ミダゾラム

PAXLOVIDは、強力なCYP3A誘導剤である薬剤と禁忌であり、ニルマトレルビルまたはリトナビルの血漿濃度が大幅に低下すると、ウイルス学的反応の喪失および耐性の可能性が失われる可能性があります。最近中止されたCYP3Aインデューサーのオフセットが遅れているため、以下の薬剤のいずれかを中止した直後にPAXLOVIDを開始することはできません[薬物相互作用(7.3)を参照]

  • 抗がん剤:アパルタミド
  • 抗けいれん薬:カルバマゼピン、フェノバルビタール、フェニトイン
  • 抗酸菌症:リファンピン
  • ハーブ製品:セントジョンズワート(セイヨウオトギリソウ

5警告と注意事項

PAXLOVIDで利用できる臨床データは限られています。PAXLOVIDの使用ではこれまで報告されていなかった、深刻で予期しない有害事象が発生する可能性があります。

5.1薬物相互作用による重篤な副作用のリスク

CYP3Aによって代謝される薬剤を投与されている患者におけるCYP3A阻害剤であるPAXLOVIDの開始、またはすでにPAXLOVIDを投与されている患者におけるCYP3Aによって代謝される薬剤の開始は、CYP3Aによって代謝される薬剤の血漿濃度を上昇させる可能性があります。

CYP3Aを阻害または誘発する薬物療法の開始は、それぞれPAXLOVIDの濃度を増加または減少させる可能性があります。

これらの相互作用は、次のことにつながる可能性があります。

  • 臨床的に重大な副作用であり、併用薬への曝露が増えると、重篤な、生命を脅かす、または致命的な事象を引き起こす可能性があります。
  • PAXLOVIDのより多くの曝露による臨床的に重大な副作用。
  • PAXLOVIDの治療効果の喪失とウイルス耐性の発生の可能性。

禁忌の薬物を含む臨床的に重要な薬物相互作用については、表1を参照してください。PAXLOVID療法の前および最中の薬物相互作用の可能性を考慮してください。PAXLOVID療法中に併用薬を確認し、併用薬に関連する副作用を監視します[禁忌(4)および薬物相互作用(7)を参照]

5.2肝毒性

リトナビルを投与されている患者では、肝トランスアミナーゼの上昇、臨床的肝炎、黄疸が発生しています。したがって、既存の肝疾患、肝酵素異常、または肝炎の患者にPAXLOVIDを投与する場合は注意が必要です。

5.3HIV-1耐性発症のリスク

ニルマトレルビルはリトナビルと同時投与されるため、HIV-1感染が制御されていない、または診断されていない個人では、HIV-1がHIVプロテアーゼ阻害剤に対する耐性を発現するリスクがある可能性があります[投与量と投与(2.4)禁忌(4)、および薬物を参照)相互作用(7) ]

6副作用

6.1臨床試験からの副作用

EUAを支持するPAXLOVIDの臨床試験では、以下の副作用が観察されています。これらの臨床試験で観察された副作用率は、他の薬剤の臨床試験での率と直接比較することはできず、臨床診療で観察された率を反映していない可能性があります。PAXLOVIDに関連する追加の有害事象は、より広く使用されると明らかになる可能性があります。

PAXLOVIDの安全性は、SARS-CoV-2感染の検査室で確認された診断を受けた、入院していない成人被験者を対象とした第2/3相ランダム化プラセボ対照試験であるC4671005試験(EPIC-HR)のデータに基づいています[臨床試験を参照] (14.1) ]。重度のCOVID-19疾患を発症するリスクが高い、18歳以上の合計2,224人の症候性成人被験者は、PAXLOVID(n = 1,109)またはプラセボ(n = 1,115)のいずれかを少なくとも1回投与されました。有害事象は、被験者が治験薬を服用している間、および治験治療を開始してから34日目までに報告されたものでした。PAXLOVID [300mgのニルマトレルビル(2つの150mgの錠剤と100mgのリトナビル]]または対応するプラセボを1日2回5日間服用しました。

プラセボ群よりも高い頻度(5人以上の被験者差)で発生したPAXLOVID群(1%以上)の有害事象(因果関係に関係なくすべてのグレード)は、味覚障害(それぞれ6%および1%未満)、下痢( 3%および2%)、高血圧(1%および<1%)、および筋肉痛(1%および<1%)。

有害事象により治療を中止した被験者の割合は、PAXLOVID群で2%、プラセボ群で4%でした。

6.4重篤な有害事象および投薬エラーについて必要な報告

処方する医療提供者および/または提供者の被指名人は、FDAフォーム3500を使用して、イベントの開始から7暦日以内にPAXLOVIDに関連する可能性のあるすべての重篤な有害事象3および投薬エラーの義務的な報告に責任を負います。このフォームにアクセスするには、以下を参照してください)。FDAは、FDAフォーム3500を使用したこのようなレポートに、以下を含めることを推奨しています。

  • 患者の人口統計およびベースライン特性(例:患者ID、生年月日、性別、体重、民族性、人種)。
  • イベント、問題、または製品の使用/投薬エラーの説明」の見出しの下にある「緊急使用許可(EUA)の下でのCOVID-19のPAXLOVID使用」というステートメント。
  • 重篤な有害事象または投薬ミスに関する情報(例、徴候と症状、検査/実験室データ、合併症、事象の発生に関連する薬物開始のタイミング、事象の期間、事象を軽減するために必要な治療、証拠投与量を停止または減らした後のイベントの改善/消失、再導入後のイベントの再発の証拠、臨床転帰)。
  • 患者の既存の病状と併用製品の使用。
  • 製品に関する情報(例、投与量、投与経路、NDC番号)。

フォーム3500を使用して、次のいずれかの方法を使用して、有害事象および投薬エラーのレポートをFDAMedWatchに送信します。

  • オンラインでレポートを完成させて提出してください:https://www.fda.gov/medwatch/report.htm
  • 郵便料金を支払ったFDAフォーム3500(https://www.fda.gov/media/76299/download)に記入して送信し、次の方法で返送してください。
    • MedWatch、5600 Fishers Lane、Rockville、MD 20852-9787、または
    • 1-800-FDA-0178にファックスするか、
  • 報告フォームをリクエストするには、1-800-FDA-1088に電話してください

さらに、すべてのFDAMedWatchフォームのコピーを次の宛先に提供してください。

Webサイトファクス番号電話番号
www.pfizersafetyreporting.com1-866-635-83371-800-438-1985

処方する医療提供者および/または提供者の被指名人は、PAXLOVIDに関連する有害事象および投薬ミスに関する情報についてのFDAからの要求に必須の応答を提供する必要があります。


3

重篤な有害事象は次のように定義されます:

  • 死亡または生命を脅かす有害事象;
  • 死亡、生命を脅かす出来事、入院、障害、または先天性異常を防ぐための医学的または外科的介入。
  • 入院または既存の入院の延長;
  • 通常の生活機能を実行する能力の持続的または重大な無能力または実質的な混乱; また
  • 先天性異常/先天性欠損症。

7薬物相互作用

7.1PAXLOVIDが他の薬剤に影響を与える可能性

PAXLOVID(リトナビルと同梱されているニルマトレルビル)はCYP3Aの阻害剤であり、主にCYP3Aによって代謝される薬物の血漿中濃度を上昇させる可能性があります。クリアランスをCYP3Aに大きく依存し、血漿濃度の上昇が重篤および/または生命を脅かす事象に関連する薬物とのPAXLOVIDの同時投与は禁忌です[禁忌(4)および表1を参照]。他のCYP3A基質との同時投与には、表1に示すように、用量調整または追加のモニタリングが必要になる場合があります。

7.2他の薬剤がPAXLOVIDに影響を与える可能性

ニルマトレルビルとリトナビルはCYP3A基質です。したがって、CYP3Aを誘発する薬剤は、ニルマトレルビルとリトナビルの血漿中濃度を低下させ、PAXLOVID治療効果を低下させる可能性があります。

7.3確立されたおよびその他の潜在的に重要な薬物相互作用

表1は、禁忌の薬物を含む、臨床的に重要な薬物相互作用のリストを示しています。表1に記載されている薬剤はガイドであり、PAXLOVIDと相互作用する可能性のあるすべての薬剤の包括的なリストとは見なされません。医療提供者は、包括的な情報について適切な参考文献を参照する必要があります[禁忌(4)を参照]

ドラッグクラスクラス内の薬物濃度への影響臨床コメント
*薬物動態、ニルマトレルビルおよびリトナビルを用いて実施された薬物相互作用研究(12.3)を参照してください。
アルファ1-アドレナリン受容体拮抗薬アルフゾシン↑アルフゾシン潜在的な低血圧のために禁忌となる同時投与[禁忌(4)を参照]
鎮痛薬ペチジン、ピロキシカム、プロポキシフェン↑ペチジン↑ピロキシカム↑プロポキシフェン重篤な呼吸抑制または血液学的異常の可能性があるため、同時投与は禁忌です[禁忌(4)を参照]
狭心症治療薬ラノラジン↑ラノラジン深刻なおよび/または生命を脅かす反応の可能性があるため、同時投与は禁忌です[禁忌(4)を参照]
抗不整脈薬アミオダロン、ドロネダロン、フレカイニド、プロパフェノン、キニジン↑抗不整脈心不整脈の可能性があるため、同時投与は禁忌です[禁忌(4)を参照]
抗不整脈薬ベプリジル、リドカイン(全身)↑抗不整脈注意が必要であり、可能であれば抗不整脈薬の治療濃度モニタリングが推奨されます。
抗がん剤アパルタミド↓ニルマトレルビル/リトナビルウイルス学的反応が失われる可能性があり、耐性が失われる可能性があるため、同時投与は禁忌です[禁忌(4)を参照]。
抗がん剤アベマシクリブ、セリチニブ、ダサチニブ、エンコラフェニブ、イブルチニブ、イボシデニブ、ネラチニブ、ニロチニブ、ベネトクラクス、ビンブラスチン、ビンクリスチン↑抗がん剤QT間隔の延長などの重篤な有害事象の潜在的なリスクがあるため、エンコラフェニブまたはイボシデニブの同時投与は避けてください。ネラチニブ、ベネトクラクスまたはイブルチニブの使用は避けてください。ビンクリスチンとビンブラスチンの同時投与は、重大な血液学的または胃腸の副作用を引き起こす可能性があります。詳細については、抗がん剤の個別の製品ラベルを参照してください。
抗凝固剤ワルファリン↑↓ワルファリンワルファリンとの同時投与が必要な場合は、INRを注意深く監視してください。
リバロキサバン↑リバロキサバンリバロキサバンによる出血リスクの増加。併用は避けてください。
抗けいれん薬カルバマゼピン*、フェノバルビタール、フェニトイン↓ニルマトレルビル/リトナビル↑カルバマゼピン↓フェノバルビタール↓フェニトインウイルス学的反応が失われる可能性があり、耐性が失われる可能性があるため、同時投与は禁忌です[禁忌(4)を参照]
抗うつ薬ブプロピオン↓ブプロピオンと活性代謝物ヒドロキシブプロピオンブプロピオンに対する適切な臨床反応を監視します。
トラゾドン↑トラゾドントラゾドンとリトナビルの同時投与後、悪心、めまい、低血圧、失神の副作用が観察されています。トラゾドンの低用量を検討する必要があります。詳細については、トラゾドン製品ラベルを参照してください。
抗真菌剤ボリコナゾール、↓ボリコナゾールボリコナゾールの併用は避けてください。
ケトコナゾール、硫酸イトラコナゾールイトラコナゾール*↑ケトコナゾール↑硫酸イトラコナゾール↑イトラコナゾール↑ニルマトレルビル/リトナビル詳細については、ケトコナゾール、硫酸イトラコナゾール、およびイトラコナゾールの製品ラベルを参照してください。
痛風防止コルヒチン↑コルヒチン腎機能障害および/または肝機能障害のある患者における重篤および/または生命を脅かす反応の可能性があるため、同時投与は禁忌です[禁忌(4)を参照]
抗HIVプロテアーゼ阻害剤アンプレナビル、アタザナビル、ダルナビル、ホスアンプレナビル、インジナビル、ネルフィナビル、サキナビル、ティプラナビル↑プロテアーゼ阻害剤詳細については、それぞれのプロテアーゼ阻害剤の処方情報を参照してください。リトナビルまたはコビシスタットを含むHIVレジメンを使用している患者は、指示に従って治療を継続する必要があります。これらのプロテアーゼ阻害剤を併用して、PAXLOVIDまたはプロテアーゼ阻害剤の有害事象の増加を監視します[投与量と投与(2.4)を参照]。
抗HIVジダノシン、デラビルジン、エファビレンツ、マラビロック、ネビラピン、ラルテグラビル、ジドブジンビクテグラビル/エムトリシタビン/テノホビル↑ジダノシン↑エファビレンツ↑マラビロク↓ラルテグラビル↓ジドブジン↑bictegravir↔エムトリシタビン↑テノホビルFor further information, refer to the respective anti-HIV drugs prescribing information.
Anti-infectiveclarithromycin,erythromycin↑ clarithromycin↑ erythromycinRefer to the respective prescribing information for anti-infective dose adjustment.
Antimycobacterialrifampin↓ nirmatrelvir/ritonavirCo-administration contraindicated due to potential loss of virologic response and possible resistance. Alternate antimycobacterial drugs such as rifabutin should be considered [see Contraindications (4)].
Antimycobacterialbedaquiline↑ bedaquilineRefer to the bedaquiline product label for further information.
rifabutin↑ rifabutinRefer to rifabutin product label for further information on rifabutin dose reduction.
Antipsychoticslurasidone,pimozide,clozapine↑ lurasidone↑ pimozide↑ clozapineCo-administration contraindicated due to serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].
Antipsychoticsquetiapine↑ quetiapineIf co-administration is necessary, reduce quetiapine dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations.
Calcium channel blockersamlodipine,diltiazem,felodipine,nicardipine,nifedipine↑ calcium channel blockerCaution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PAXLOVID.If co-administered, refer to individual product label for calcium channel blocker for further information.
Cardiac glycosidesdigoxin↑ digoxinCaution should be exercised when co-administering PAXLOVID with digoxin, with appropriate monitoring of serum digoxin levels.Refer to the digoxin product label for further information.
Endothelin receptor Antagonistsbosentan↑ bosentanDiscontinue use of bosentan at least 36 hours prior to initiation of PAXLOVID.Refer to the bosentan product label for further information.
Ergot derivativesdihydroergotamine,ergotamine,methylergonovine↑ dihydroergotamine↑ ergotamine↑ methylergonovineCo-administration contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4)].
Hepatitis C direct acting antiviralselbasvir/grazoprevir,glecaprevir/pibrentasvir↑ antiviralIncreased grazoprevir concentrations can result in ALT elevations.It is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir.
ombitasvir/paritaprevir/ritonavir and dasabuvirRefer to the ombitasvir/paritaprevir/ritonavir and dasabuvir label for further information.
sofosbuvir/velpatasvir/voxilaprevirRefer to the sofosbuvir/velpatasvir/voxilaprevir product label for further information.Patients on ritonavir-containing HCV regimens should continue their treatment as indicated. Monitor for increased PAXLOVID or HCV drug adverse events with concomitant use [see Dosage and Administration (2.4)].
Herbal productsSt. John’s Wort (hypericum perforatum)↓ nirmatrelvir/ritonavirCo-administration contraindicated due to potential loss of virologic response and possible resistance [see Contraindications (4)].
HMG-CoA reductase inhibitorslovastatin,simvastatin↑ lovastatin↑ simvastatinCo-administration contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4)].Discontinue use of lovastatin and simvastatin at least 12 hours prior to initiation of PAXLOVID.
HMG-CoA reductase inhibitorsatorvastatin,rosuvastatin↑ atorvastatin↑ rosuvastatinConsider temporary discontinuation of atorvastatin and rosuvastatin during treatment with PAXLOVID.
Hormonal contraceptiveethinyl estradiol↓ ethinyl estradiolAn additional, non-hormonal method of contraception should be considered.
Immunosuppressantscyclosporine,tacrolimus,sirolimus↑ cyclosporine↑ tacrolimus↑ sirolimusTherapeutic concentration monitoring is recommended for immunosuppressants.Avoid use of PAXLOVID when close monitoring of immunosuppressant serum concentrations is not feasible.Avoid concomitant use of sirolimus and PAXLOVID.If co-administered, refer to individual product label for immunosuppressant for further information.
Long-acting beta-adrenoceptor agonistsalmeterol↑ salmeterolCo-administration is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Narcotic analgesicsfentanyl↑ fentanylCareful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with PAXLOVID.
methadone↓ methadoneMonitor methadone-maintained patients closely for evidence of withdrawal effects and adjust the methadone dose accordingly.
PDE5 inhibitorsildenafil (Revatio®) when used for pulmonary arterial hypertension↑ sildenafilCo-administration contraindicated due to the potential for sildenafil associated adverse events, including visual abnormalities hypotension, prolonged erection, and syncope [see Contraindications (4)].
Sedative/hypnoticstriazolam,oral midazolam↑ triazolam↑ midazolamCo-administration contraindicated due to potential for extreme sedation and respiratory depression [see Contraindications (4)].
Sedative/hypnoticsmidazolam (administered parenterally)↑ midazolamCo-administration of midazolam (parenteral) should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.Refer to the midazolam product label for further information.
Systemic corticosteroidsbetamethasone,budesonide,ciclesonide,dexamethasone,fluticasone,methylprednisolone,mometasone,prednisone,triamcinolone↑ corticosteroidIncreased risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone should be considered.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available human data on the use of nirmatrelvir during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published observational studies on ritonavir use in pregnant women have not identified an increase in the risk of major birth defects. Published studies with ritonavir are insufficient to identify a drug-associated risk of miscarriage (see Data). There are maternal and fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations).

In an embryo-fetal development study with nirmatrelvir, reduced fetal body weights following oral administration of nirmatrelvir to pregnant rabbits were observed at systemic exposures (AUC) approximately 10 times higher than clinical exposure at the authorized human dose of PAXLOVID. No other adverse developmental outcomes were observed in animal reproduction studies with nirmatrelvir at systemic exposures (AUC) greater than or equal to 3 times higher than clinical exposure at the authorized human dose of PAXLOVID (see Data).

In animal reproduction studies with ritonavir, no evidence of adverse developmental outcomes was observed following oral administration of ritonavir to pregnant rats and rabbits at doses (based on body surface area conversions) or systemic exposures (AUC) greater than or equal to 3 times higher than clinical doses or exposure at the authorized human dose of PAXLOVID (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated Maternal and/or Embryo-fetal Risk

COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.

Data

Human Data

Ritonavir

Based on prospective reports to the antiretroviral pregnancy registry of live births following exposure to ritonavir-containing regimens (including over 3,400 live births exposed in the first-trimester and over 3,500 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The prevalence of birth defects in live births was 2.3% (95% confidence interval [CI]: 1.9%–2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%–3.6%) following second and third trimester exposure to ritonavir-containing regimens. While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.

Animal Data

Nirmatrelvir

Embryo-fetal developmental (EFD) toxicity studies were conducted in pregnant rats and rabbits administered oral nirmatrelvir doses of up to 1,000 mg/kg/day during organogenesis [on Gestation Days (GD) 6 through 17 in rats and 6 through 19 in rabbits]. No biologically significant developmental effects were observed in the rat EFD study. At the highest dose of 1,000 mg/kg/day, the systemic nirmatrelvir exposure (AUC24) in rats was approximately 8 times higher than clinical exposures at the authorized human dose of PAXLOVID. In the rabbit EFD study, lower fetal body weights (9% decrease) were observed at 1,000 mg/kg/day in the absence of significant maternal toxicity findings. At 1,000 mg/kg/day, the systemic exposure (AUC24) in rabbits was approximately 10 times higher than clinical exposures at the authorized human dose of PAXLOVID. No other significant developmental toxicities (malformations and embryo-fetal lethality) were observed at up to the highest dose tested, 1,000 mg/kg/day. No developmental effects were observed in rabbits at 300 mg/kg/day resulting in systemic exposure (AUC24) approximately 3 times higher than clinical exposures at the authorized human dose of PAXLOVID. A pre- and postnatal developmental (PPND) study in pregnant rats administered oral nirmatrelvir doses of up to 1,000 mg/kg/day from GD 6 through Lactation Day (LD) 20 is ongoing and only interim data through postnatal day (PND) 56 are currently available. Although no difference in body weight was noted at birth when comparing offspring born to nirmatrelvir treated versus control animals, a decrease (8% in males and females) in the body weight of offspring was observed at PND 17. No significant differences in offspring body weight were observed from PND 28 to PND 56. The maternal systemic exposure (AUC24) at 1,000 mg/kg/day was approximately 8 times higher than clinical exposures at the authorized human dose of PAXLOVID. No body weight changes in the offspring were noted at 300 mg/kg/day, resulting in systemic exposure (AUC24) approximately 5 times higher than clinical exposures at the authorized human dose of PAXLOVID.

Ritonavir

Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on GD 6 through 17 and 6 through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at systemic exposures (AUC) approximately 4 times higher than exposure at the authorized human dose of PAXLOVID. Increased incidences of early resorptions, ossification delays, and developmental variations, as well as decreased fetal body weights were observed in rats in the presence of maternal toxicity, at systemic exposures approximately 4 times higher than exposure at the authorized human dose of PAXLOVID. A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose) at an exposure approximately 5 times the exposure at the authorized human dose of PAXLOVID. In rabbits, resorptions, decreased litter size, and decreased fetal weights were observed at maternally toxic doses approximately 11 times higher than the authorized human dose of PAXLOVID, based on a body surface area conversion factor. In a pre- and postnatal development study in rats, administration of 0, 15, 35, and 60 mg/kg/day ritonavir from GD 6 through postnatal day 20 resulted in no developmental toxicity, at ritonavir doses 3 times higher than the authorized human dose of PAXLOVID, based on a body surface area conversion factor.

8.2 Lactation

Risk Summary

There are no available data on the presence of nirmatrelvir in human or animal milk, the effects on the breastfed infant, or the effects on milk production. A transient decrease in body weight was observed in the nursing offspring of rats administered nirmatrelvir (see Data). Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PAXLOVID and any potential adverse effects on the breastfed infant from PAXLOVID or from the underlying maternal condition. Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.

Data

In the pre- and postnatal developmental study, body weight decreases (up to 8%) were observed in the offspring of pregnant rats administered nirmatrelvir at maternal systemic exposure (AUC24) approximately 8 times higher than clinical exposures at the authorized human dose of PAXLOVID. No body weight changes in the offspring were noted at maternal systemic exposure (AUC24) approximately 5 times higher than clinical exposures at the authorized human dose of PAXLOVID.

8.3 Females and Males of Reproductive Potential

Contraception

Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.3)].

8.4 Pediatric Use

PAXLOVID is not authorized for use in pediatric patients younger than 12 years of age or weighing less than 40 kg. The safety and effectiveness of PAXLOVID have not been established in pediatric patients. The authorized adult dosing regimen is expected to result in comparable serum exposures of nirmatrelvir and ritonavir in patients 12 years of age and older and weighing at least 40 kg as observed in adults, and adults with similar body weight were included in the trial EPIC-HR [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

8.5 Geriatric Use

Clinical studies of PAXLOVID include subjects 65 years of age and older and their data contributes to the overall assessment of safety and efficacy [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. Of the total number of subjects in EPIC-HR randomized to receive PAXLOVID (N=1,120), 13% were 65 years of age and older and 3% were 75 years of age and older.

8.6 Renal Impairment

Systemic exposure of nirmatrelvir increases in renally impaired patients with increase in the severity of renal impairment [see Clinical Pharmacology (12.3)].

No dosage adjustment is needed in patients with mild renal impairment. In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), reduce the dose of PAXLOVID to 150 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions [see Patient Counseling Information (17)].

PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min based on CKD-EPI formula) until more data are available; the appropriate dosage for patients with severe renal impairment has not been determined.

8.7 Hepatic Impairment

No dosage adjustment of PAXLOVID is needed for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, PAXLOVID is not recommended for use in patients with severe hepatic impairment [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Treatment of overdose with PAXLOVID should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with PAXLOVID.

11 DESCRIPTION

PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. Nirmatrelvir is a SARS-CoV-2 main protease (Mpro) inhibitor, and ritonavir is an HIV-1 protease inhibitor and CYP3A inhibitor.

Nirmatrelvir

The chemical name of active ingredient of nirmatrelvir is (1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide]. It has a molecular formula of C23H32F3N5O4 and a molecular weight of 499.54. Nirmatrelvir has the following structural formula:

Chemical Structure

Nirmatrelvir is available as immediate-release, film-coated tablets. Each tablet contains 150 mg nirmatrelvir with the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, and sodium stearyl fumarate. The following are the ingredients in the film coating: hydroxy propyl methylcellulose, iron oxide red, polyethylene glycol, and titanium dioxide.

Ritonavir

Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1 methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir has the following structural formula:

Chemical Structure

Ritonavir is available as film-coated tablets. Each tablet contains 100 mg ritonavir with the following inactive ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The following are the ingredients in the film coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders it incapable of processing polyprotein precursors, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro in a biochemical assay with a Ki value of 3.1 nM and an IC50 value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-ray crystallography.

Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2 Mpro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.

12.3 Pharmacokinetics

The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy subjects.

Ritonavir is administered with nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemic concentrations and longer half-life of nirmatrelvir, thereby supporting a twice daily administration regimen.

Upon oral administration of nirmatrelvir/ritonavir, the increase in systemic exposure appears to be less than dose proportional up to 750 mg as a single dose and up to 500 mg twice daily as multiple doses. Twice daily dosing over 10 days achieved steady-state on Day 2 with approximately 2-fold accumulation. The pharmacokinetic properties of nirmatrelvir/ritonavir are displayed in Table 2.

Nirmatrelvir (When Given With Ritonavir)Ritonavir
*Represents data after a single dose of 300 mg nirmatrelvir (2 × 150 mg tablet formulation) administered together with 100 mg ritonavir tablet in healthy subjects.Red blood cell to plasma ratio.300 mg nirmatrelvir (oral suspension formulation) and 100 mg ritonavir (tablet formulation) administered together twice a day for 3 days.§Nirmatrelvir is a CYP3A4 substrate but when dosed with ritonavir metabolic clearance is minimal.Determined by 19F-NMR analysis following 300 mg oral suspension enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours, and 24 hours.#Determined by 14C analysis following 600 mg 14C-ritonavir oral solution.
Absorption
Tmax (h), median3.00*3.98*
Distribution
% bound to human plasma proteins69%98–99%
Blood-to-plasma ratio0.600.14
Vz/F (L), mean104.7112.4
Elimination
Major route of eliminationRenal elimination§Hepatic metabolism
Half-life (t1/2) (hr), mean6.05*6.15*
Oral clearance (CL/F), mean8.9913.92
Metabolism
Metabolic pathwaysMinimal§Major CYP3A4, Minor CYP2D6
Excretion
% drug-related material in feces49.6%86.4%#
% drug-related material in urine35.3%11.3%#

Single dose pharmacokinetic data of PAXLOVID in healthy subjects is depicted below (Table 3).

PK Parameter (units)Nirmatrelvir(N=12)
Represents data from 2 × 150 mg tablets of nirmatrelvir. Values are presented as geometric mean (geometric % CV) except median (range) for Tmax and arithmetic mean ± SD for T1/2.
Cmax (µg/mL)2.21 (33)
AUCinf (µg*hr/mL)23.01 (23)
Tmax (hr)3.00 (1.02–6.00)
T1/2 (hr)6.05 ± 1.79

Effect of Food on Oral Absorption of Nirmatrelvir

Dosing with a high fat meal modestly increased the exposure of nirmatrelvir (approximately 15% increase in mean Cmax and 1.6% increase in mean AUClast) relative to fasting conditions following administration of a suspension formulation of nirmatrelvir co-administered with ritonavir tablets.

Specific Populations

The pharmacokinetics of nirmatrelvir/ritonavir based on age and gender have not been evaluated.

Pediatric Patients

The pharmacokinetics of nirmatrelvir/ritonavir in patients less than 18 years of age have not been evaluated.

Using a population PK model, the dosing regimen is expected to result in comparable steady-state plasma exposure of nirmatrelvir in patients 12 years of age and older and weighing at least 40 kg to those observed in adults after adjusting for body weight.

Racial or Ethnic Groups

Systemic exposure in Japanese subjects was numerically lower but not clinically meaningfully different than those in Western subjects.

Patients with Renal Impairment

An open-label study compared nirmatrelvir/ritonavir pharmacokinetics in healthy adult subjects and subjects with mild (eGFR ≥60 to <90 mL/min), moderate (eGFR ≥30 to <60 mL/min), and severe (eGFR <30 mL/min) renal impairment following administration of a single oral dose of nirmatrelvir 100 mg enhanced with ritonavir 100 mg administered at -12, 0, 12, and 24 hours. Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in patients with mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was 38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher, respectively (Table 4).

Normal Renal Function(n=8)Mild Renal Impairment(n=8)Moderate Renal Impairment(n=8)Severe Renal Impairment(n=8)
Values are presented as geometric mean (geometric % CV) except median (range) for Tmax and arithmetic mean ± SD for t1/2.
Cmax (µg/mL)1.60 (31)2.08 (29)2.21 (17)2.37 (38)
AUCinf (µg*hr/mL)14.46 (20)17.91 (30)27.11 (27)44.04 (33)
Tmax (hr)2.0 (1.0 – 4.0)2.0 (1.0 – 3.0)2.50 (1.0 – 6.0)3.0 (1.0 – 6.1)
T1/2 (hr)7.73 ± 1.826.60 ± 1.539.95 ± 3.4213.37 ± 3.32

Patients with Hepatic Impairment

A single oral dose of 100 mg nirmatrelvir enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours and 24 hours in subjects with moderate hepatic impairment resulted in similar exposures compared to subjects with normal hepatic function (Table 5).

Normal Hepatic Function(n=8)Moderate Hepatic Impairment(n=8)
Values are presented as geometric mean (geometric % CV) except median (range) for Tmax and arithmetic mean ± SD for t1/2.
Cmax (µg/mL)1.89 (20)1.92 (48)
AUCinf (µg*hr/mL)15.24 (36)15.06 (43)
Tmax (hr)2.0 (0.6 – 2.1)1.5 (1.0 – 2.0)
T1/2 (hr)7.21 ± 2.105.45 ± 1.57

Nirmatrelvir/ritonavir has not been studied in patients with severe hepatic impairment.

Drug Interaction Studies Conducted with Nirmatrelvir

In vitro data indicates that nirmatrelvir is a substrate for human MDR1 (P-gp) and 3A4, but not a substrate for human BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, OATPs 1B1, 1B3, 2B1, or 4C1.

Nirmatrelvir does not reversibly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 in vitro at clinically relevant concentrations. Nirmatrelvir has the potential to reversibly and time-dependently inhibit CYP3A4 and inhibit MDR1 (P-gp).

Nirmatrelvir does not induce any CYPs at clinically relevant concentrations.

Drug Interaction Studies Conducted with Ritonavir

In vitro studies indicate that ritonavir is mainly a substrate of CYP3A. Ritonavir also appears to be a substrate of CYP2D6 which contributes to the formation of isopropylthiazole oxidation metabolite M-2.

Ritonavir is an inhibitor of CYP3A and to a lesser extent CYP2D6. Ritonavir appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.

The effects of co-administration of PAXLOVID with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and Cmax are summarized in Table 6 (effect of other drugs on nirmatrelvir).

Co-administered DrugDose (Schedule)NRatio (in combination with Co-administered drug/alone) of Nirmatrelvir Pharmacokinetic Parameters (90% CI);No Effect=100
Co-administered DrugNirmatrelvir/RitonavirCmaxAUC*
Abbreviations: AUC=area under the plasma concentration-time curve; CI=confidence interval; Cmax=maximum plasma concentrations.
*For carbamazepine, AUC=AUCinf, for itraconazole, AUC=AUCtau.Carbamazepine titrated up to 300 mg twice daily on Day 8 through Day 15 (e.g., 100 mg twice daily on Day 1 through Day 3 and 200 mg twice daily on Day 4 through Day 7).
Carbamazepine300 mg twice daily(16 doses)300 mg/100 mg twice daily(5 doses)956.82(47.04, 68.62)44.50(33.77, 58.65)
Itraconazole200 mg once daily(8 doses)300 mg/100 mg twice daily(5 doses)11118.57(112.50, 124.97)138.82(129.25, 149.11)

12.4 Microbiology

Antiviral Activity

Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 (USA-WA1/2020 isolate) infection of differentiated normal human bronchial epithelial (dNHBE) cells with EC50 and EC90 values of 62 nM and 181 nM, respectively, after 3 days of drug exposure.

Nirmatrelvir had similar cell culture antiviral activity (EC50 values ≤3-fold relative to USA-WA1/2020) against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Lambda (C.37) variants. The Beta (B.1.351) variant was the least susceptible tested variant with approximately 3-fold reduced susceptibility relative to the USA-WA1/2020 isolate.

No data are available regarding the activity of nirmatrelvir against the SARS-CoV-2 Omicron (B.1.1.529) variant in cell culture. However, in a biochemical assay, the Mpro P132H substitution found in the Omicron variant did not reduce nirmatrelvir activity (Ki fold change <1) compared to the USA-WA1/2020 enzyme.

Antiviral Activity Against SARS-CoV-2 in Animal Models

Nirmatrelvir showed antiviral activity in BALB/c and 129 mice infected with mouse-adapted SARS-CoV-2. Oral administration of nirmatrelvir at 300 mg/kg or 1,000 mg/kg twice daily initiated 4 hours post-inoculation or 1,000 mg/kg twice daily initiated 12 hours post-inoculation resulted in reduction of lung viral titers and ameliorated indicators of disease (weight loss and lung pathology) compared to placebo-treated animals.

Antiviral Resistance

Phenotypic assessments were conducted to characterize the impact of naturally occurring SARS-CoV-2 Mpro polymorphisms on the activity of nirmatrelvir in a biochemical assay using recombinant Mpro enzyme. The clinical significance of these polymorphisms is unknown, and it is also unknown if results from the biochemical assay are predictive of antiviral activity in cell culture. The following Mpro amino acid substitutions were associated with reduced nirmatrelvir activity (≥3-fold higher Ki values): G15S (4.4-fold), T135I (3.5-fold), S144A (91.9-fold), H164N (6.4-fold), H172Y (233-fold), Q189K (65.4-fold), and D248E (3.7-fold). G15S is present in the Lambda variant, which did not have reduced susceptibility to nirmatrelvir (relative to USA-WA1/2020) in cell culture.

In addition, three SARS-CoV-2 Mpro amino acid positions where polymorphisms have not been naturally observed were evaluated by substituting alanine at these positions and assessing their impact on activity in biochemical assays. These Mpro amino acid substitutions were associated with reduced nirmatrelvir activity (i.e., higher Ki values): Y54A (23.6-fold), F140A (39.0-fold), and E166A (33.4-fold). The clinical significance of substitutions at these Mpro positions is unknown.

Cell culture resistance selection studies with nirmatrelvir using mouse hepatitis virus (MHV, a betacoronavirus used as a surrogate) resulted in the emergence of Mpro amino acid substitutions P15A, T50K, P55L, T129M, and/or S144A. The clinical relevance of these changes is not known. The presence of the substitutions P55L and S144A was associated with reduced nirmatrelvir susceptibility (~4- to 5-fold higher EC50 values). These positions correspond to E55 and S144 in SARS-CoV-2 Mpro, respectively. E55L alone did not affect nirmatrelvir activity against SARS-CoV-2 Mpro in a biochemical assay, while S144A reduced nirmatrelvir activity by 91.9-fold (based on Ki value).

Limited SARS-CoV-2 sequencing data are available to characterize nirmatrelvir resistance in clinical trials. The SARS-CoV-2 Mpro substitutions A260V (n=3) or A260T (n=1) emerged in 4% (4/97) of nirmatrelvir/ritonavir treated subjects in clinical trial EPIC-HR with available sequence analysis data. A260T and A260V substitutions are infrequent natural polymorphisms in publicly available SARS-CoV-2 sequences (as of Dec 5, 2021). In a biochemical assay, the A260V Mpro substitution did not reduce nirmatrelvir activity (Ki fold-change <1).

Cross-resistance is not expected between nirmatrelvir and anti-SARS-CoV-2 monoclonal antibodies or remdesivir based on their different mechanisms of action.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Nirmatrelvir

Carcinogenicity studies have not been conducted with nirmatrelvir.

Nirmatrelvir was negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the in vitro micronucleus assay using human lymphoblastoid TK6 cells, and the in vivo rat micronucleus assays.

In a fertility and early embryonic development study, nirmatrelvir was administered orally to male and female rats at doses of 60, 200, or 1,000 mg/kg/day once daily beginning 14 days prior to mating, throughout the mating phase, and continued through GD 6 for females and for a total of 32 doses for males. There were no effects on fertility, reproductive performance, or early embryonic development at doses up to 1,000 mg/kg/day, resulting in systemic exposure (AUC24) approximately 4 times higher than exposure at the authorized human dose of PAXLOVID.

Ritonavir

Carcinogenicity studies in mice and rats have been conducted on ritonavir. In male mice, at levels of 50, 100, or 200 mg/kg/day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 2 times higher (in males) than the exposure in humans at the authorized human dose of PAXLOVID. There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 4 times higher (in females) than the exposure in humans at the authorized human dose of PAXLOVID. In rats dosed at levels of 7, 15, or 30 mg/kg/day, there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 36% that of the exposure in humans at the authorized human dose of PAXLOVID.

Ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Ritonavir produced no effects on fertility in rats at drug exposures approximately 2 (male) and 4 (female) times higher than the exposure in humans at the authorized human dose of PAXLOVID.

13.2 Animal Toxicology and/or Pharmacology

Studies with nirmatrelvir included repeat dose toxicity studies in rats (14 days) and monkeys (15 days). Repeated daily oral dosing in rats at up to 1,000 mg/kg/day resulted in non-adverse hematological, liver, and thyroid effects. All of the hematology and coagulation findings (i.e., increases in PT and APTT) had no clinical or microscopic correlates and all findings completely recovered at the end of the 2-week recovery period. The liver (i.e., minimal to mild periportal hepatocyte hypertrophy and vacuolation) and thyroid gland (i.e., thyroid follicular cell hypertrophy) findings were consistent with secondary adaptive effects related to microsomal enzyme-induced increase in thyroid hormone clearance in the liver, a mechanism that rats are known to be particularly sensitive to relative to humans. All of the findings observed in the liver and thyroid were low severity and occurred in the absence of correlating alterations in clinical pathology parameters, and all of these findings fully recovered. No adverse effects were observed at doses up to 1,000 mg/kg/day, resulting in systemic exposure approximately 4 times higher than exposures at the authorized human dose of PAXLOVID. Nirmatrelvir-related findings following repeat oral dosing in monkeys for 15 days were limited to emesis and increase in fibrinogen. Increased fibrinogen may be attributed to an inflammatory state but lacked a microscopic correlate. At the high dose of 600 mg/kg/day, the systemic exposure in monkeys was about 18 times higher than exposures at the authorized human dose of PAXLOVID.

14 CLINICAL STUDIES

14.1 Efficacy in Subjects at High Risk of Progressing to Severe COVID-19 Illness

The data supporting this EUA are based on the analysis of EPIC-HR (NCT04960202), a Phase 2/3, randomized, double-blind, placebo-controlled study in non-hospitalized symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age and older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically-related technological dependence, or were 60 years of age and older regardless of comorbidities. Subjects with COVID-19 symptom onset of ≤5 days were included in the study. Subjects were randomized (1:1) to receive PAXLOVID (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo orally every 12 hours for 5 days. The study excluded individuals with a history of prior COVID-19 infection or vaccination. The primary efficacy endpoint was the proportion of subjects with COVID-19 related hospitalization or death from any cause through Day 28. The analysis was conducted in the modified intent-to-treat (mITT) analysis set (all treated subjects with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), the mITT1 analysis set (all treated subjects with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated subjects with onset of symptoms ≤5 days).

A total of 2,246 subjects were randomized to receive either PAXLOVID or placebo. At baseline, mean age was 46 years; 51% were male; 72% were White, 5% were Black, and 14% were Asian; 45% were Hispanic or Latino; 66% of subjects had onset of symptoms ≤3 days from initiation of study treatment; 47% of subjects were serological negative at baseline; the mean (SD) baseline viral load was 4.63 log10 copies/mL (2.87); 26% of subjects had a baseline viral load of >10^7 (units); 6% of subjects either received or were expected to receive COVID-19 therapeutic monoclonal antibody treatment at the time of randomization and were excluded from the mITT and mITT1 analyses.

The baseline demographic and disease characteristics were balanced between the PAXLOVID and placebo groups.

Table 7 provides results of the primary endpoint in mITT1 analysis population. For the primary endpoint, the relative risk reduction in the mITT1 analysis population for PAXLOVID compared to placebo was 88% (95% CI: 75%, 94%).

PAXLOVID(N=1,039)Placebo(N=1,046)
Abbreviations: CI=confidence interval.The determination of primary efficacy was based on a planned interim analysis of 780 subjects in mITT population. The estimated risk reduction was -6.3% with a 95% CI of (-9.0%, -3.6%) and 2-sided p-value <0.0001.
*The estimated cumulative proportion of participants hospitalized or death by Day 28 was calculated for each treatment group using the Kaplan-Meier method, where subjects without hospitalization and death status through Day 28 were censored at the time of study discontinuation.
COVID-19 related hospitalization or death from any cause through Day 28
n (%)8 (0.8%)66 (6.3%)
Reduction relative to placebo* [95% CI], %-5.62 (-7.21, -4.03)
All-cause mortality through Day 28, %012 (1.1%)

Consistent results were observed in the mITT and mITT2 analysis populations. A total of 1,379 subjects were included in the mITT analysis population. The event rates were 5/697 (0.72%) in the PAXLOVID group, and 44/682 (6.45%) in the placebo group. The primary SARS-CoV-2 variant across both treatment arms was Delta (98%), including clades 21J, 21A, and 21I.

Similar trends have been observed across subgroups of subjects (see Figure 1). These subgroup analyses are considered exploratory.

Figure 1: Adults with COVID-19 Dosed within 5 Days of Symptom Onset with COVID-19-Related Hospitalization or Death from Any Cause Through Day 28 (Protocol C4671005)

Figure 1

N=number of participants in the category of the analysis set.

All categories are based on mITT1 population except for COVID-19 mAb treatment which is based on mITT2 population.

Seropositivity was defined if results were positive in either Elecsys anti-SARS-CoV-2 S or Elecsys anti-SARS-CoV-2 (N) assay.

The difference of the proportions in the 2 treatment groups and its 95% confidence interval based on Normal approximation of the data are presented.

Relative to placebo, PAXLOVID treatment was associated with an approximately 0.9 log10 copies/mL greater decline in viral RNA levels in nasopharyngeal samples through Day 5, with similar results observed in the mITT, mITT1, and mITT2 analysis populations.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets.

  • Nirmatrelvir tablets, 150 mg are oval, pink immediate-release, film-coated tablets debossed with “PFE” on one side and “3CL” on the other side.
  • Ritonavir tablets, 100 mg are white film-coated ovaloid tablets debossed with the “a” logo and the code NK.

Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card.

Each carton contains 30 tablets divided in 5 daily-dose blister cards (NDC number: 0069-1085-30).

Each daily blister card (NDC number: 0069-1085-06) contains 4 nirmatrelvir tablets (150 mg each) and 2 ritonavir tablets (100 mg each) and indicates which tablets need to be taken in the morning and evening.

Storage and Handling

Store at USP controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

17 PATIENT COUNSELING INFORMATION

As a healthcare practitioner, you must communicate to the patient and/or caregiver information consistent with the “FACT SHEET FOR PATIENTS, PARENTS, AND CAREGIVERS” and provide them with a copy of this Fact Sheet prior to administration of PAXLOVID.

Use in Patients with Renal Impairment

No dose adjustment is needed in patients with mild renal impairment.

To ensure appropriate dosing in patients with moderate renal impairment, instruct such patients that they will be taking one 150 mg nirmatrelvir tablet with one 100 mg ritonavir tablet together twice daily for 5 days. Instruct patients that the pharmacist will alter their daily blister cards to ensure they receive the correct dose.

Pharmacist should refer to the provided instructions entitled “IMPORTANT PAXLOVID™ EUA DISPENSING INFORMATION FOR PATIENTS WITH MODERATE RENAL IMPAIRMENT” for dispensing of PAXLOVID to patients with moderate renal impairment [see Dosage and Administration (2.2)].

Appropriate dosage for patients with severe renal impairment has not been determined [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Drug Interactions

Inform patients that PAXLOVID may interact with some drugs and is contraindicated for use with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication, or herbal products [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)].

Administration Instructions

Inform patients to take PAXLOVID with or without food as instructed. Advise patients to swallow all tablets for PAXLOVID whole and not to chew, break, or crush the tablets. Alert the patient of the importance of completing the full 5-day treatment course and to continuing isolation in accordance with public health recommendations to maximize viral clearance and minimize transmission of SARS-CoV-2. If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose [see Dosage and Administration (2.1)].

18 MANUFACTURER INFORMATION

For general questions, visit the website or call the telephone number provided below.

WebsiteTelephone number
www.COVID19oralRx.comQR code1-877-219-7225(1-877-C19-PACK)

For Medical Information about PAXLOVID, please visit www.pfizermedinfo.com or call 1-800-438-1985.

Logo

LAB-1492-1.0

Revised: 22 Dec 2021

FACT SHEET FOR PATIENTS, PARENTS, AND CAREGIVERS

EMERGENCY USE AUTHORIZATION (EUA) OF PAXLOVID

FOR CORONAVIRUS DISEASE 2019 (COVID-19)

You are being given this Fact Sheet because your healthcare provider believes it is necessary to provide you with PAXLOVID for the treatment of mild-to-moderate coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus. This Fact Sheet contains information to help you understand the risks and benefits of taking the PAXLOVID you have received or may receive.

The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) to make PAXLOVID available during the COVID-19 pandemic (for more details about an EUA please see “What is an Emergency Use Authorization?” at the end of this document). PAXLOVID is not an FDA-approved medicine in the United States. Read this Fact Sheet for information about PAXLOVID. Talk to your healthcare provider about your options or if you have any questions. It is your choice to take PAXLOVID.

What is COVID-19?

COVID-19 is caused by a virus called a coronavirus. You can get COVID-19 through close contact with another person who has the virus.

COVID-19 illnesses have ranged from very mild-to-severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness can happen and may cause some of your other medical conditions to become worse. Older people and people of all ages with severe, long lasting (chronic) medical conditions like heart disease, lung disease, and diabetes, for example seem to be at higher risk of being hospitalized for COVID-19.

What is PAXLOVID?

PAXLOVID is an investigational medicine used to treat mild-to-moderate COVID-19 in adults and children [12 years of age and older weighing at least 88 pounds (40 kg)] with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. PAXLOVID is investigational because it is still being studied. There is limited information about the safety and effectiveness of using PAXLOVID to treat people with mild-to-moderate COVID-19.

The FDA has authorized the emergency use of PAXLOVID for the treatment of mild-to- moderate COVID-19 in adults and children [12 years of age and older weighing at least 88 pounds (40 kg)] with a positive test for the virus that causes COVID-19, and who are at high risk for progression to severe COVID-19, including hospitalization or death, under an EUA.

What should I tell my healthcare provider before I take PAXLOVID?

Tell your healthcare provider if you:

  • Have any allergies
  • Have liver or kidney disease
  • Are pregnant or plan to become pregnant
  • Are breastfeeding a child
  • Have any serious illnesses

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some medicines may interact with PAXLOVID and may cause serious side effects. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.

You can ask your healthcare provider or pharmacist for a list of medicines that interact with PAXLOVID. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take PAXLOVID with other medicines.

Tell your healthcare provider if you are taking combined hormonal contraceptive. PAXLOVID may affect how your birth control pills work. Females who are able to become pregnant should use another effective alternative form of contraception or an additional barrier method of contraception. Talk to your healthcare provider if you have any questions about contraceptive methods that might be right for you.

How do I take PAXLOVID?

  • PAXLOVID consists of 2 medicines: nirmatrelvir and ritonavir.
    • Take 2 pink tablets of nirmatrelvir with 1 white tablet of ritonavir by mouth 2 times each day (in the morning and in the evening) for 5 days. For each dose, take all 3 tablets at the same time.
    • If you have kidney disease, talk to your healthcare provider. You may need a different dose.
  • Swallow the tablets whole. Do not chew, break, or crush the tablets.
  • Take PAXLOVID with or without food.
  • Do not stop taking PAXLOVID without talking to your healthcare provider, even if you feel better.
  • If you miss a dose of PAXLOVID within 8 hours of the time it is usually taken, take it as soon as you remember. If you miss a dose by more than 8 hours, skip the missed dose and take the next dose at your regular time. Do not take 2 doses of PAXLOVID at the same time.
  • If you take too much PAXLOVID, call your healthcare provider or go to the nearest hospital emergency room right away.
  • If you are taking a ritonavir- or cobicistat-containing medicine to treat hepatitis C or Human Immunodeficiency Virus (HIV), you should continue to take your medicine as prescribed by your healthcare provider.

Talk to your healthcare provider if you do not feel better or if you feel worse after 5 days.

Who should generally not take PAXLOVID?

Do not take PAXLOVID if:

  • You are allergic to nirmatrelvir, ritonavir, or any of the ingredients in PAXLOVID.
  • You are taking any of the following medicines:
    • Alfuzosin
    • Pethidine, piroxicam, propoxyphene
    • Ranolazine
    • Amiodarone, dronedarone, flecainide, propafenone, quinidine
    • Colchicine
    • Lurasidone, pimozide, clozapine
    • Dihydroergotamine, ergotamine, methylergonovine
    • Lovastatin, simvastatin
    • Sildenafil (Revatio®) for pulmonary arterial hypertension (PAH)
    • Triazolam, oral midazolam
    • Apalutamide
    • Carbamazepine, phenobarbital, phenytoin
    • Rifampin
    • St. John’s Wort (hypericum perforatum)

Taking PAXLOVID with these medicines may cause serious or life-threatening side effects or affect how PAXLOVID works.

These are not the only medicines that may cause serious side effects if taken with PAXLOVID. PAXLOVID may increase or decrease the levels of multiple other medicines. It is very important to tell your healthcare provider about all of the medicines you are taking because additional laboratory tests or changes in the dose of your other medicines may be necessary while you are taking PAXLOVID. Your healthcare provider may also tell you about specific symptoms to watch out for that may indicate that you need to stop or decrease the dose of some of your other medicines.

What are the important possible side effects of PAXLOVID?

Possible side effects of PAXLOVID are:

  • Liver Problems. Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems: loss of appetite, yellowing of your skin and the whites of eyes (jaundice), dark-colored urine, pale colored stools and itchy skin, stomach area (abdominal) pain.
  • Resistance to HIV Medicines. If you have untreated HIV infection, PAXLOVID may lead to some HIV medicines not working as well in the future.
  • Other possible side effects include:
    • altered sense of taste
    • diarrhea
    • high blood pressure
    • muscle aches

These are not all the possible side effects of PAXLOVID. Not many people have taken PAXLOVID. Serious and unexpected side effects may happen. PAXLOVID is still being studied, so it is possible that all of the risks are not known at this time.

What other treatment choices are there?

Like PAXLOVID, FDA may allow for the emergency use of other medicines to treat people with COVID-19. Go to https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization for information on the emergency use of other medicines that are authorized by FDA to treat people with COVID-19. Your healthcare provider may talk with you about clinical trials for which you may be eligible.

It is your choice to be treated or not to be treated with PAXLOVID. Should you decide not to receive it or for your child not to receive it, it will not change your standard medical care.

What if I am pregnant or breastfeeding?

There is no experience treating pregnant women or breastfeeding mothers with PAXLOVID. For a mother and unborn baby, the benefit of taking PAXLOVID may be greater than the risk from the treatment. If you are pregnant, discuss your options and specific situation with your healthcare provider.

It is recommended that you use effective barrier contraception or do not have sexual activity while taking PAXLOVID.

If you are breastfeeding, discuss your options and specific situation with your healthcare provider.

How do I report side effects with PAXLOVID?

Contact your healthcare provider if you have any side effects that bother you or do not go away.

Report side effects to FDA MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088 or you can report side effects to Pfizer Inc. at the contact information provided below.

WebsiteFax numberTelephone number
www.pfizersafetyreporting.com1-866-635-83371-800-438-1985

How should I store PAXLOVID?

Store PAXLOVID tablets at room temperature, between 68°F to 77°F (20°C to 25°C).

How can I learn more about COVID-19?

  • Ask your healthcare provider.
  • Visit https://www.cdc.gov/COVID19.
  • Contact your local or state public health department.

What is an Emergency Use Authorization (EUA)?

The United States FDA has made PAXLOVID available under an emergency access mechanism called an Emergency Use Authorization (EUA). The EUA is supported by a Secretary of Health and Human Service (HHS) declaration that circumstances exist to justify the emergency use of drugs and biological products during the COVID-19 pandemic.

PAXLOVID for the treatment of mild-to-moderate COVID-19 in adults and children [12 years of age and older weighing at least 88 pounds (40 kg)] with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, has not undergone the same type of review as an FDA-approved product. In issuing an EUA under the COVID-19 public health emergency, the FDA has determined, among other things, that based on the total amount of scientific evidence available including data from adequate and well-controlled clinical trials, if available, it is reasonable to believe that the product may be effective for diagnosing, treating, or preventing COVID-19, or a serious or life-threatening disease or condition caused by COVID-19; that the known and potential benefits of the product, when used to diagnose, treat, or prevent such disease or condition, outweigh the known and potential risks of such product; and that there are no adequate, approved, and available alternatives.

All of these criteria must be met to allow for the product to be used in the treatment of patients during the COVID-19 pandemic. The EUA for PAXLOVID is in effect for the duration of the COVID-19 declaration justifying emergency use of this product, unless terminated or revoked (after which the products may no longer be used under the EUA).

Additional Information

For general questions, visit the website or call the telephone number provided below.

WebsiteTelephone number
www.COVID19oralRx.comQR Code1-877-219-7225(1-877-C19-PACK)

You can also go to www.pfizermedinfo.com or call 1-800-438-1985 for more information.

Logo

LAB-1494-1.0

Revised: 22 December 2021

Revised: 12/2021

Pfizer Laboratories Div Pfizer Inc

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